1h-pyrazolo[4,3-b]pyridines as pde1 inhibitors

ABSTRACT

The present invention provides 1H-pyrazolo[4,3-b]pyridines of formula (I) as PDE1 inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

Foreign priority benefits are claimed under 35 U.S.C. § 119(a)-(d) or 35U.S.C. § 365(b) of Danish application number PA201700727, filed Dec. 20,2017, and Danish application number PA201700730, filed Dec. 20, 2017.The entire contents of these applications are incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

The present invention provides compounds that are PDE1 enzyme inhibitorsand their use as a medicament, in particular for the treatment ofneurodegenerative disorders and psychiatric disorders. The presentinvention also provides pharmaceutical compositions comprising compoundsof the invention and methods of treating disorders using the compoundsof the invention.

BACKGROUND OF THE INVENTION

The second messenger cyclic Nucleotides (cNs), cyclic adenosinemonophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play amajor role in intracellular signal transduction cascade, by regulatingcN-dependent protein kinases (PKA and PKG), EPACs (Exchange ProteinActivated by cAMP), phosphoprotein phosphatases, and/or cN-gated cationchannels. In neurons, this includes the activation of cAMP- andcGMP-dependent kinases and subsequent phosphorylation of proteinsinvolved in acute regulation of synaptic transmission as well as inneuronal differentiation and survival. Intracellular concentrations ofcAMP and cGMP are strictly regulated by the rate of biosynthesis bycyclases and by the rate of degradation by phosphodiesterases (PDEs, EC3.1.4.17). PDEs are bimetallic hydrolases that inactivate cAMP/cGMP bycatalytic hydrolysis of the 3′-ester bond, forming the inactive5′-monophosphate. Since PDEs provide the only means of degrading thecyclic nucleotides cAMP and cGMP in cells, PDEs play an essential rolein cyclic nucleotide signalling. The catalytic activities of PDEsprovide for breakdown of cNs over a spectrum of cN-concentrations in allcells, and their varied regulatory mechanisms provide for integrationand crosstalk with myriads of signalling pathways. Particular PDEs aretargeted to discrete compartments within cells where they control cNlevel and sculpt microenvironments for a variety of cN signalosomes(Sharron H. Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev2011, 91: 651-690).

On the basis of substrate specificity, the PDE families can be dividedinto three groups: 1) The cAMP-specific PDEs, which include PDE4, PDE7,and PDE8, 2) the cGMP-selective enzymes PDE5 and PDE9, and 3) thedual-substrate PDEs, PDE1, PDE2, PDE3, as well as PDE10 and PDE11.

Previously named calmodulin-stimulated PDE (CaM-PDE), PDE1 is unique inthat it is Ca²⁺-dependently regulated via calmodulin (CaM, a 16 kDaCa²⁺-binding protein) complexed with four Ca²⁺ (for review, Sharron H.Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev 2011, 91:651-690). Thus, PDE1 represents an interesting regulatory link betweencyclic nucleotides and intracellular Ca²⁺. The PDE1 family is encoded bythree genes: PDE1A (mapped on human chromosome 2q32), PDE1B (humanchromosome location, hcl: 12q13) and PDE1C (hcl: 7p14.3). They havealternative promoters and give rise to a multitude of proteins byalternative splicing which differ in their regulatory properties,substrate affinities, specific activities, activation constants for CaM,tissue distribution and molecular weights. More than 10 human isoformsare identified. Their molecular weights vary from 58 to 86 kDa permonomer. The N-terminal regulatory domain contains two Ca²⁺/CaM bindingdomains and two phosphorylation sites and different splice variants havedifferent variations of the N-terminal domain, which can give proteinswith different amino acid sequence with different biochemical functions.PDE1 is a dual substrate PDE and the PDE1C-subtype has equal activitytowards cAMP and cGMP (Km≈1-3 μM), whereas the subtypes PDE1A and PDE1Bhave a preference for cGMP (Km for cGMP≈1-3 μM and for cAMP≈10-30 μM).

The PDE1 subtypes are highly enriched in the brain and locatedespecially in the striatum (PDE1B), hippocampus (PDE1A) and cortex(PDE1A) and this localization is conserved across species (Amy Bernardet al. Neuron 2012, 73, 1083-1099). In the cortex, PDE1A is presentmainly in deep cortical layers 5 and 6 (output layers), and used as aspecificity marker for the deep cortical layers. PDE1 inhibitors enhancethe levels of the second messenger cNs leading to enhanced neuronalexcitability.

Thus, PDE1 is a therapeutic target for regulation of intracellularsignalling pathways, preferably in the nervous system and PDE1inhibitors can enhance the levels of the second messenger's cAMP/cGMPleading to modulation of neuronal processes and to the expression ofneuronal plasticity-related genes, neurotrophic factors, andneuroprotective molecules. These neuronal plasticity enhancementproperties together with the modulation of synaptic transmission makePDE1 inhibitors good candidates as therapeutic agents in manyneurological and psychiatric conditions. The evaluation of PDE1inhibitors in animal models (for reviews see e.g. Blokland et al. ExpertOpinion on Therapeutic Patents (2012), 22(4), 349-354; and Medina, A. E.Frontiers in Neuropharmacology (2011), 5(February), 21) has suggestedthe potential for the therapeutic use of PDE1 inhibitors in neurologicaldisorders, like e.g. Alzheimer's, Parkinson's and Huntington's Diseasesand in psychiatric disorders like e.g. Attention Deficit HyperactivityDisorder (ADHD), depression, anxiety, narcolepsy, cognitive impairmentand cognitive impairment associated with schizophrenia (CIAS) and inrestless leg syndrome. There have also been patent applications claimingthat PDE1 inhibitors are useful in diseases that may be alleviated bythe enhancement of progesterone-signalling such as female sexualdysfunction (e.g. WO 2008/070095).

Current treatments for neurodegenerative and/or psychiatric disordersare not efficacious in all patients. Hence, there remains a need foralternative methods of treatment of such diseases and for this purposePDE1 inhibitors may be a good alternative. The present inventiondiscloses new compounds with PDE1 inhibitor activity and goodphysicochemical properties as alternatives to known PDE1 inhibitors.

SUMMARY OF THE INVENTION

PDE1 enzymes are expressed in the Central Nervous System (CNS), makingthis gene family an attractive source of new targets for the treatmentof psychiatric and neurodegenerative disorders.

Accordingly, the present invention relates to a compound according toformula (I)

wherein

-   L is selected from the group consisting of NH, CH₂, S and O;-   R1 is selected from the group consisting of hydrogen, linear or    branched C₁₋₅ alkyl, C₁₋₅ fluoroalkyl and saturated monocyclic C₃₋₅    cycloalkyl;-   R2 is selected from the group consisting of linear or branched C₁₋₈    alkyl, saturated monocyclic C₃₋₈ cycloalkyl, oxetanyl,    tetrahydrofuranyl, and tetrahydropyranyl; all of which can be    optionally substituted one or more times with one or more    substituents selected from the group consisting of methyl, fluorine,    hydroxy, cyano and methoxy;-   the combination of R3 and R4 are selected from a) and b):    -   a) R3 is methyl substituted with a 9-membered bicyclic        heteroaryl which is optionally substituted with one or more        substituents selected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃        fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or        -   R3 is ethyl substituted with a 9-membered bicyclic            heteroaryl which is optionally substituted with one or more            substituents selected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃            fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or        -   L is CH₂ and R3 is NH which is substituted with a 9-membered            bicyclic heteroaryl which is optionally substituted with one            or more substituents selected from halogen, cyano, C₁₋₃            alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy;        -   R4 is phenyl, pyridinyl, pyridazinyl or pyridonyl all of            which can be optionally substituted one or more times with            one or more substituents selected from the group consisting            of halogen, cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄            deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃            alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6 wherein R5 and R6            are each independently selected from H, C₁₋₃ alkyl and C₁₋₃            deuterioalkyl; or        -   R4 is a 5-membered heteroaryl which is optionally            substituted with one or more substituents selected from            halogen, cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄            deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃            alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6 wherein R5 and R6            are each independently selected from H, C₁₋₃ alkyl and C₁₋₃            deuterioalkyl; or        -   R4 is a 4, 5 or 6 membered saturated heterocycle all of            which can be optionally substituted with one or more            substituents selected from oxo, C₁₋₄ alkyl and C₁₋₄            fluoroalkyl;    -   b) R3 is methyl substituted with phenyl, pyridonyl, pyridinyl,        pyrimidinyl or pyrazinyl all of which can be optionally        substituted one or more times with one or more substituents        selected from the group consisting of halogen, cyano, C₁₋₃        alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or        -   R3 is methyl substituted with a 5-membered heteroaryl which            is optionally substituted with one or more substituents            selected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl,            C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or        -   R3 is ethyl substituted with phenyl, pyridonyl, pyridinyl,            pyrimidinyl or pyrazinyl all of which can be optionally            substituted one or more times with one or more substituents            selected from the group consisting of halogen, cyano, C₁₋₃            alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy;            or        -   R3 is ethyl substituted with a 5-membered heteroaryl which            is optionally substituted with one or more substituents            selected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl,            C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or        -   L is CH₂ and R3 is NH which is substituted with phenyl,            pyridonyl, pyridinyl, pyrimidinyl or pyrazinyl all of which            can be optionally substituted one or more times with one or            more substituents selected from the group consisting of            halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃            fluoroalkoxy and C₁₋₃ alkoxy; or        -   L is CH₂ and R3 is NH which is substituted with a 5-membered            heteroaryl which is optionally substituted with one or more            substituents selected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃            fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy;        -   R4 is pyridazinyl which can be optionally substituted one or            more times with one or more substituents selected from the            group consisting of halogen, cyano, C₁₋₄ alkyl, C₁₋₄            fluoroalkyl, C₁₋₄ deuterioalkyl, C₁₋₃ fluoroalkoxy,            cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6            wherein R5 and R6 are each independently selected from H,            C₁₋₃ alkyl and C₁₋₃ deuterioalkyl; or        -   R4 is 4-pyridinyl which can be optionally substituted one or            more times with one or more substituents selected from the            group consisting of halogen, cyano, C₁₋₄ alkyl, C₁₋₄            fluoroalkyl, C₁₋₄ deuterioalkyl, C₁₋₃ fluoroalkoxy,            cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6            wherein R5 and R6 are each independently selected from H,            C₁₋₃ alkyl and C₁₋₃ deuterioalkyl; or        -   R4 is a 9-membered bicyclic heteroaryl which can be            optionally substituted one or more times with one or more            substituents selected from the group consisting of halogen,            cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ deuterioalkyl,            C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃            deuterioalkoxy and —N—R5R6 wherein R5 and R6 are each            independently selected from H, C₁₋₃ alkyl and C₁₋₃            deuterioalkyl;-   or a pharmaceutically acceptable salt thereof.

Reference to compounds encompassed by the present invention includes thefree base and pharmaceutically acceptable salts of the compounds, suchas acid addition salts of the compounds, racemic mixtures of thecompounds, or the corresponding enantiomer and/or optical isomer of thecompounds for which this is relevant, and polymorphic and amorphic formsof compounds of the present invention and of pharmaceutically acceptablesalts of said compounds, as well as tautomeric forms the compounds forwhich this is relevant. Furthermore, the compounds of the presentinvention and pharmaceutically acceptable salts thereof may potentiallyexist in unsolvated as well as in solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol and the like. Both solvatedand unsolvated forms of the compounds and pharmaceutically acceptablesalts thereof are encompassed by the present invention.

In one embodiment, the invention relates to a compound according toformula (I) or a pharmaceutically acceptable salt thereof for use intherapy.

In one embodiment, the invention relates to a compound according toformula (I) or a pharmaceutically acceptable salt thereof, for use inthe treatment of a neurodegenerative disorder, selected from the groupconsisting of Alzheimer's Disease, Parkinson's Disease and Huntington'sDisease or for use in the treatment of a psychiatric disorder such asAttention Deficit Hyperactivity Disorder (ADHD), depression, anxiety,narcolepsy, cognitive impairment and cognitive impairment associatedwith schizophrenia (CIAS), or another brain disease like restless legsyndrome.

In one embodiment, the invention relates to a pharmaceutical compositioncomprising a compound according formula (I) or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptablecarrier and/or excipient.

In one embodiment, the invention relates to a method for the treatmentof a neurodegenerative disorder, selected from the group consisting ofAlzheimer's Disease, Parkinson's Disease and Huntington's Disease or forthe treatment of a psychiatric disorder such as Attention DeficitHyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,cognitive impairment and cognitive impairment associated withschizophrenia (CIAS), or another brain disease like restless legsyndrome, which method comprises the administration of a therapeuticallyeffective amount of a compound according to formula (I) or apharmaceutically acceptable salt thereof, to a patient in need thereof.

In one embodiment, the invention relates to the use of a compoundaccording to formula (I) or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for the treatment of aneurodegenerative disorder, selected from the group consisting ofAlzheimer's Disease, Parkinson's Disease and Huntington's Disease or forthe treatment of a psychiatric disorder such as Attention DeficitHyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,cognitive impairment and cognitive impairment associated withschizophrenia (CIAS), or another brain disease like restless legsyndrome.

Definitions PDE1 Enzymes:

The PDE1 isozyme family includes numerous splice variant PDE1 isoforms.It has three subtypes, PDE1A, PDE1B and PDE1C which divide further intovarious isoforms. In the context of the present invention PDE1 and PDE1enzymes are synonymous and refer to PDE1A, PDE1B and PDE1C enzymes aswell as their isoforms unless otherwise specified.

PDE1 Inhibitors:

In the context of the present invention, a compound is considered to bea PDE1 inhibitor if the amount required to reach the ICso level of oneor more of the three PDE1 isoforms is 10 micro molar or less, preferablyless than 9 micro molar, such as 8 micro molar or less, such as 7 micromolar or less, such as 6 micro molar or less, such as 5 micro molar orless, such as 4 micro molar or less, such as 3 micro molar or less, morepreferably 2 micro molar or less, such as 1 micro molar or less, inparticular 500 nM or less.

Preferred compounds of the invention exhibit selectivity towards thePDE1B isoform meaning that said compounds are stronger as PDE1Binhibitors than as PDE1A and/or PDE1C inhibitors. In preferredembodiments, said compounds are at least two-fold stronger, five-foldstronger or ten-fold stronger as PDE1B inhibitors than as PDE1A and/orPDE1C inhibitors. In more preferred embodiments, said compounds are atleast fifteen-fold stronger or twenty-fold stronger as PDE1B inhibitorsthan as PDE1A and/or PDE1C inhibitors.

In preferred embodiments, the required amount of PDE1 inhibitor requiredto reach the IC₅₀ level of PDE1B is 400 nM or less, such as 300 nM orless, 200 nM or less, 100 nM or less, or even 80 nM or less, such as 50nM or less, for example 25 nM or less. Selectivity towards the PDE1Bisoform may prevent potentially unwanted effects associated with PDE1Aand/or PDE1C inhibition. For example, potentially unwanted peripheraleffects.

Substituents:

In the present context, “optionally substituted” means that theindicated moiety may or may not be substituted, and when substituted ismono-, di-, or tri-substituted. It is understood that where nosubstituents are indicated for an “optionally substituted” moiety, thenthe position is held by a hydrogen atom.

As used in the context of the present invention, the terms “halo” and“halogen” are used interchangeably and refer to fluorine, chlorine,bromine or iodine. In a preferable embodiment, “halogen” refers tofluorine.

A given range may interchangeably be indicated with “-” (dash) or “to”,e.g. the term “C₁₋₃ alkyl” is equivalent to “C₁ to C₃ alkyl”.

The terms “C₁₋₃ alkyl”, “C₁₋₄ alkyl”, “C₁₋₅ alkyl”, “C₁₋₆ alkyl”, “C₁₋₇alkyl” and “C₁₋₈ alkyl” refer to a linear (i.e. unbranched) or branchedsaturated hydrocarbon having from one up to eight carbon atoms,inclusive. Examples of such groups include, but are not limited to,methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl,2-methyl-1-butyl, n-hexyl, n-heptyl and n-octyl.

The term “C₁₋₃ fluoroalkyl” refers to a C₁₋₃ alkyl substituted with oneor more fluorine.

The term saturated monocyclic C₃₋₈ cycloalkyl refers to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term “5-membered heteroaryl” refers to a 5 membered aromaticmonocyclic ring containing 1 to 4 carbon atoms and one or moreheteroatoms selected from oxygen, nitrogen and sulfur. Examples include,but are not limited to thiazolyl, oxazolyl, isoxazolyl, triazolyl,pyrazolyl, tetrazolyl, imidazolyl, oxadiazolyl and thiadiazolyl andthiophenyl.

The term “9-membered bicyclic heteroaryl” refers to a moiety consistingof a 6-membered aromatic ring and a 5-membered aromatic ring fusedtogether to give a 9-membered bicyclic aromatic moeity. The 9-memberedbicyclic heteroaryl consists of carbon and one or more heteroatomsselected from oxygen, nitrogen and sulfur. Particular mention is made ofbenzoxazolyl, imidazo[1,5-a]pyridine,imidazo[1,2-a]pyridine, indazolyl,and indolyl.

The term “C₁₋₃ alkoxy” refers to a moiety of the formula —OR′, whereinR′ indicates C₁-C₃ alkyl as defined above.

The term “C₁₋₃ fluoroalkoxy” refers to a moiety of the formula —OR′,wherein R′ indicates C₁-C₃ fluoroalkyl as defined above.

The terms, “C₁₋₄ deuterioalkyl” and “C₁₋₃ deuterioalkyl” refer to a C₁₋₄alkyl and a C₁₋₃ alkyl wherein one or more hydrogen atoms are designatedas deuterium. Examples of “C₁₋₃ deuterioalkyl” include, but are notlimited to, trideuteriomethyl, 1,1-dideuterioethyl,2,2,2-trideuterioethyl and 1,1,2,2,2-pentadeuterioethyl.

The term, “C₁₋₃ deuterioalkoxy” refers to a C₁₋₃ alkoxy wherein one ormore hydrogen atoms are designated as deuterium. Wxamples include, butare not limited to, trideuteriomethoxy, 1,1-dideuterioethoxy,2,2,2-trideuterioethoxy and 1,1,2,2,2-pentadeuterioethoxy.

The terms “4, 5 or 6 membered saturated heterocycle” refers to asaturated monocyclic ring containing 1 to 3, 4, or 5 carbon atoms andone or more heteroatoms selected from oxygen, nitrogen and sulfur.Examples include, but are not limited to oxazolidin-2-one,azetidin-2-one, imidazolidin-2-one, pyrrolidin-2-one,imidazolidine-2,4-dione, oxazolidine-2,4-dione or piperidin-2-one.

The term “9-membered bicyclic heteroaryl” refers to a moiety consistingof a 6-membered aromatic ring and a 5-membered aromatic ring fusedtogether to give a 9-membered bicyclic aromatic moeity. The 9-memberedbicyclic heteroaryl consists of carbon and one or more heteroatomsselected from oxygen, nitrogen and sulfur. Particular mention is made ofbenzoxazol, imidazo[1,5-a]pyridine and imidazo[1,2-a]pyridine.

Isomeric and Tautomeric Forms:

When compounds of the present invention contain one or more chiralcenters reference to any of the compounds will, unless otherwisespecified, cover the enantiomerically or diastereomerically purecompound as well as mixtures of the enantiomers or diastereomers in anyratio.

When a compound of the invention is denoted with the suffix “enantiomer1” or “enantiomer 2” it is understood that said enantiomer could beeither the S-enantiomer or the R-enantiomer. I.e. “enantiomer 1” couldbe either the S-enantiomer or the R-enantiomer and “enantiomer 2” couldbe either the S-enantiomer or the R-enantiomer. When both enantiomer 1and enantiomer 2 have been exemplified for a compound it follows thatone is the S-enantiomer and the other is the R-enantiomer.

The absolute stereochemistry for a compound of the invention can bedetermined by X-ray crystallography or vibrational circular dichroism.

Furthermore, some of the compounds of the present invention may exist indifferent tautomeric forms and it is intended that any tautomeric formsthat the compounds are able to form are included within the scope of thepresent invention.

Pharmaceutically Acceptable Salts:

The compounds of this invention are generally utilized as the freesubstance or as a pharmaceutically acceptable salt thereof. When acompound of formula (I) contains a free base, such salts are prepared ina conventional manner by treating a solution or suspension of a freebase of formula (I) with a molar equivalent of a pharmaceuticallyacceptable acid. Representative examples of suitable organic andinorganic acids are described below.

Pharmaceutically acceptable salts in the present context is intended toindicate non-toxic, i.e. physiologically acceptable salts. The termpharmaceutically acceptable salts includes salts formed with inorganicand/or organic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, nitrous acid, sulphuric acid, benzoic acid, citricacid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaricacid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaricacid, glutamic acid, pyroglutamic acid, salicylic acid, salicylic acid,saccharin and sulfonic acids, such as methanesulfonic acid,ethanesulfonic acid, toluenesulfonic acid and benzenesulfonic acid. Someof the acids listed above are di- or tri-acids, i.e. acids containingtwo or three acidic hydrogens, such as phosphoric acid, sulphuric acid,fumaric acid and maleic acid.

Additional examples of useful acids and bases to form pharmaceuticallyacceptable salts can be found e.g. in Stahl and Wermuth (Eds) “Handbookof Pharmaceutical salts. Properties, selection, and use”, Wiley-VCH,2008.

Therapeutically Effective Amount:

In the present context, the term “therapeutically effective amount” of acompound means an amount sufficient to alleviate, arrest, partly arrest,remove or delay the clinical manifestations of a given disease and itscomplications in a therapeutic intervention comprising theadministration of said compound. An amount adequate to accomplish thisis defined as “therapeutically effective amount”. Effective amounts foreach purpose will depend on the severity of the disease or injury aswell as the weight and general state of the subject. It will beunderstood that determining an appropriate dosage may be achieved usingroutine experimentation, by constructing a matrix of values and testingdifferent points in the matrix, which is all within the ordinary skillsof a trained physician.

Treatment and Treating:

In the present context, “treatment” or “treating” is intended toindicate the management and care of a patient for the purpose ofalleviating, arresting, partly arresting, removing or delaying progressof the clinical manifestation of the disease. The patient to be treatedis preferably a mammal, in particular a human being.

Combinations

In one embodiment of the invention, the compound of formula (I) is foruse as stand-alone treatment as the sole active compound.

In another embodiment of the invention, the compound of formula (I) maybe used in combination with a second compound, wherein said secondcompound is selected from the following: a compound useful in active orpassive Tau immunotherapy, a compound useful in active or passive APpeptide immunotherapy, an NMDA receptor antagonist, an acetylcholineesterase inhibitor, a BACE inhibitor, a 5-HT6 receptor antagonist, anantiepileptic, an anti-inflammatory drug or an anti-N3-pGlu Abetamonoclonal antibody.

In yet another embodiment of the invention, the compound of formula (I)may be used in combination with a second compound, wherein said secondcompound is a compound that is useful in the treatment of a psychiatricdisorder.

The terms “combined use”, “in combination with” and “a combination of”and the like as used herein in the context of the method of theinvention comprising the combined administration of therapeuticallyeffective amounts of a compound of formula (I), and anotherpharmaceutically active compound, is intended to mean the administrationof a compound of formula (I) simultaneously or sequentially, in anyorder, together with said second compound.

The two compounds may be administered simultaneously or with a time gapbetween the administrations of the two compounds. The two compounds maybe administered either as part of the same pharmaceutical formulation orcomposition, or in separate pharmaceutical formulations or compositions.The two compounds may be administered on the same day or on differentdays. They may be administered by the same route, such for example byoral administration, by depot, by intramuscular injection or intravenousinjection; or by different routes wherein one compound is for exampleadministered orally or placed by depot and the other compound is forexample injected. The two compounds may be administered by the samedosage regime or interval, such as once or twice daily, weekly, ormonthly; or by different dosage regimes for example wherein one isadministered once daily and the other is administered twice daily orweekly or monthly.

In some instances, the patient to be treated may already be in treatmentwith one or more of said second compound when treatment with a compoundof formula (I) is initiated. In other instances, the patient may alreadybe in treatment with a compound of formula (I) when treatment with oneor more of said second compound is initiated. In other instances, thetreatment with a compound of formula (I) and treatment with one or moreof said second compound is initiated at the same time.

Compounds for Combination Treatment

In the context of the invention, compounds to be used in combinationwith a compound of formula (I) in the treatment of a neurodegenerativedisorder, are selected from for example a compound useful in active orpassive Tau immunotherapy, a compound useful in active or passive Aβpeptide immunotherapy, an NMDA receptor antagonist, an acetylcholineesterase inhibitor, a BACE inhibitor, a 5-HT6 receptor antagonist, anantiepileptic, an anti-inflammatory drug or an anti-N3-pGlu Abetamonoclonal antibody.

In the context of the invention, compounds to be used in combinationwith a compound of formula (I) in the treatment of a psychiatric and/orcognitive disorder, is a compound with a pharmacological activityselected from one or more of the following mechanisms:antagonist/inverse agonist/negative modulator/partial agonist/inhibitorof one or more of the targets dopamine D1 receptor, dopamine D2receptor, dopamine D3 receptor, phosphodiesterase PDE10, serotonin5-HT2A receptor, serotonin 5-HT6 receptor, and glycine transporterGlyT1; or agonist/positive modulator/partial agonist of one or more ofthe targets KCNQ channels, NMDA receptor, AMPA receptor and nicotinicalpha-7 receptor. Examples of such compounds includes clozapine,risperidone, paliperidone, olanzapine, quetiapine, amisulpride,ziprasidone, aripiprazole, brexpiprazole, asenapine, haloperidole,iloperidone, lurasidone, chlorpromazine, blonanserin, perphenazine,levomepromazine, sulpiride, fluphenazine, zuclopenthixol, flupenthixoland cariprazine.

Administration Routes:

Pharmaceutical compositions comprising a compound of the presentinvention either as the sole active compound or in combination a secondcompound defined above, may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,buccal, sublingual, transdermal and parenteral (e.g. subcutaneous,intramuscular, and intravenous) route; the oral route being preferred.

It will be appreciated that the route will depend on the generalcondition and age of the subject to be treated, the nature of thecondition to be treated and the active ingredient.

Pharmaceutical Formulations and Excipients:

In the following, the term, “excipient” or “pharmaceutically acceptableexcipient” refers to pharmaceutical excipients including, but notlimited to, fillers, antiadherents, binders, coatings, colours,disintegrants, flavours, glidants, lubricants, preservatives, sorbents,sweeteners, solvents, vehicles and adjuvants.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), such as one of the compoundsdisclosed in the Experimental Section herein. The present invention alsoprovides a process for making a pharmaceutical composition comprising acompound of formula (I). The pharmaceutical compositions according tothe invention may be formulated with pharmaceutically acceptableexcipients in accordance with conventional techniques such as thosedisclosed in Remington, “The Science and Practice of Pharmacy”, 22^(th)edition (2012), Edited by Allen, Loyd V., Jr.

Pharmaceutical compositions for oral administration include solid oraldosage forms such as tablets, capsules, powders and granules; and liquidoral dosage forms such as solutions, emulsions, suspensions and syrupsas well as powders and granules to be dissolved or suspended in anappropriate liquid.

Solid oral dosage forms may be presented as discrete units (e.g. tabletsor hard or soft capsules), each containing a predetermined amount of theactive ingredient, and preferably one or more suitable excipients. Whereappropriate, the solid dosage forms may be prepared with coatings suchas enteric coatings or they may be formulated so as to provide modifiedrelease of the active ingredient such as delayed or extended releaseaccording to methods well known in the art. Where appropriate, the soliddosage form may be a dosage form disintegrating in the saliva, such asfor example an orodispersible tablet.

Examples of excipients suitable for solid oral formulation include, butare not limited to, microcrystalline cellulose, corn starch, lactose,mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin,talcum, gelatin, pectin, magnesium stearate, stearic acid and loweralkyl ethers of cellulose. Similarly, the solid formulation may includeexcipients for delayed or extended release formulations known in theart, such as glyceryl monostearate or hypromellose. If solid material isused for oral administration, the formulation may for example beprepared by mixing the active ingredient with solid excipients andsubsequently compressing the mixture in a conventional tabletingmachine; or the formulation may for example be placed in a hard capsulee.g. in powder, pellet or mini tablet form. The amount of solidexcipient will vary widely but will typically range from about 25 mg toabout 1 g per dosage unit.

Liquid oral dosage forms may be presented as for example elixirs,syrups, oral drops or a liquid filled capsule. Liquid oral dosage formsmay also be presented as powders for a solution or suspension in anaqueous or non-aqueous liquid. Examples of excipients suitable forliquid oral formulation include, but are not limited to, ethanol,propylene glycol, glycerol, polyethylenglycols, poloxamers, sorbitol,poly-sorbate, mono and di-glycerides, cyclodextrins, coconut oil, palmoil, and water. Liquid oral dosage forms may for example be prepared bydissolving or suspending the active ingredient in an aqueous ornon-aqueous liquid, or by incorporating the active ingredient into anoil-in-water or water-in-oil liquid emulsion.

Further excipients may be used in solid and liquid oral formulations,such as colourings, flavourings and preservatives etc.

Pharmaceutical compositions for parenteral administration includesterile aqueous and nonaqueous solutions, dispersions, suspensions oremulsions for injection or infusion, concentrates for injection orinfusion as well as sterile powders to be reconstituted in sterilesolutions or dispersions for injection or infusion prior to use.Examples of excipients suitable for parenteral formulation include, butare not limited to water, coconut oil, palm oil and solutions ofcyclodextrins. Aqueous formulations should be suitably buffered ifnecessary and rendered isotonic with sufficient saline or glucose.

Other types of pharmaceutical compositions include suppositories,inhalants, creams, gels, dermal patches, implants and formulations forbuccal or sublingual administration.

It is requisite that the excipients used for any pharmaceuticalformulation comply with the intended route of administration and arecompatible with the active ingredients.

Doses:

In one embodiment, the compound of the present invention is administeredin an amount from about 0.001 mg/kg body weight to about 100 mg/kg bodyweight per day. In particular, daily dosages may be in the range of 0.01mg/kg body weight to about 50 mg/kg body weight per day. The exactdosages will depend upon the frequency and mode of administration, thesex, the age, the weight, and the general condition of the subject to betreated, the nature and the severity of the condition to be treated, anyconcomitant diseases to be treated, the desired effect of the treatmentand other factors known to those skilled in the art.

A typical oral dosage for adults will be in the range of 0.1-1000 mg/dayof a compound of the present invention, such as 1-500 mg/day, such as1-100 mg/day or 1-50 mg/day. Conveniently, the compounds of theinvention are administered in a unit dosage form containing saidcompounds in an amount of about 0.1 to 500 mg, such as 10 mg, 50 mg 100mg, 150 mg, 200 mg or 250 mg of a compound of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have identified compounds that are PDE1inhibitors, and as such are useful to treat neurodegenerative andpsychiatric disorders. The present invention thus provides compounds offormula (I) that are effective in inhibiting PDE1 for use as amedicament in the treatment of a mammal, preferably a human.

The invention provides a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, as well as a pharmaceutical compositioncontaining such a compound, for use in the treatment of a brain diseasewhich could be a neurodegenerative disorder or a psychiatric disorder.In a preferred embodiment, the neurodegenerative disorder is selectedfrom the group consisting of Alzheimer's Disease, Parkinson's Diseaseand Huntington's Disease. In another preferred embodiment, thepsychiatric disorder is selected from the group consisting of AttentionDeficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,cognitive impairment and cognitive impairment associated withschizophrenia (CIAS). Other brain disorders could be e.g. restless legsyndrome.

This invention further provides a method of treating a brain diseasewhich could be a neurodegenerative or a psychiatric disorder, whichmethod comprises administering to said mammal a pharmaceuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof. Examples of neurodegenerative disorders thatcan be treated according to the present invention include Alzheimer'sDisease, Parkinson's Disease and Huntington's Disease, which methodcomprises administering to the subject a therapeutically effectiveamount of a compound of formula (I). Examples of psychiatric disordersthat can be treated according to the present invention include AttentionDeficit Hyperactivity Disorder (ADHD), depression, narcolepsy, cognitiveimpairment and cognitive impairment associated with schizophrenia(CTAS). Other brain disorders to be treated could be e.g. restless legsyndrome.

Embodiments of the Invention

In the following, embodiments of the invention are disclosed. The firstembodiment is denoted E1, the second embodiment is denoted E2 and soforth.

-   E1. A compound according to formula (I)

-   wherein-   L is selected from the group consisting of NH, CH₂, S and O;-   R1 is selected from the group consisting of hydrogen, linear or    branched C₁₋₅ alkyl, C₁₋₅ fluoroalkyl and saturated monocyclic C₃₋₅    cycloalkyl;

R2 is selected from the group consisting of linear or branched C₁₋₈alkyl, saturated monocyclic C₃₋₈ cycloalkyl, oxetanyl,tetrahydrofuranyl, and tetrahydropyranyl; all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of methyl, fluorine, hydroxy, cyano andmethoxy;

-   the combination of R3 and R4 are selected from a) and b):    -   a) R3 is methyl substituted with a 9-membered bicyclic        heteroaryl which is optionally substituted with one or more        substituents selected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃        fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or        -   R3 is ethyl substituted with a 9-membered bicyclic            heteroaryl which is optionally substituted with one or more            substituents selected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃            fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or        -   L is CH₂ and R3 is NH which is substituted with a 9-membered            bicyclic heteroaryl which is optionally substituted with one            or more substituents selected from halogen, cyano, C₁₋₃            alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy;        -   R4 is phenyl, pyridinyl, pyridazinyl or pyridonyl all of            which can be optionally substituted one or more times with            one or more substituents selected from the group consisting            of halogen, cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄            deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃            alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6 wherein R5 and R6            are each independently selected from H, C₁₋₃ alkyl and C₁₋₃            deuterioalkyl; or        -   R4 is a 5-membered heteroaryl which is optionally            substituted with one or more substituents selected from            halogen, cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄            deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃            alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6 wherein R5 and R6            are each independently selected from H, C₁₋₃ alkyl and C₁₋₃            deuterioalkyl; or        -   R4 is a 4, 5 or 6 membered saturated heterocycle all of            which can be optionally substituted with one or more            substituents selected from oxo, C₁₋₄ alkyl and C₁₋₄            fluoroalkyl;    -   b) R3 is methyl substituted with phenyl, pyridonyl, pyridinyl,        pyrimidinyl or pyrazinyl all of which can be optionally        substituted one or more times with one or more substituents        selected from the group consisting of halogen, cyano, C₁₋₃        alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or        -   R3 is methyl substituted with a 5-membered heteroaryl which            is optionally substituted with one or more substituents            selected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl,            C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or        -   R3 is ethyl substituted with phenyl, pyridonyl, pyridinyl,            pyrimidinyl or pyrazinyl all of which can be optionally            substituted one or more times with one or more substituents            selected from the group consisting of halogen, cyano, C₁₋₃            alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy;            or        -   R3 is ethyl substituted with a 5-membered heteroaryl which            is optionally substituted with one or more substituents            selected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl,            C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or        -   L is CH₂ and R3 is NH which is substituted with phenyl,            pyridonyl, pyridinyl, pyrimidinyl or pyrazinyl all of which            can be optionally substituted one or more times with one or            more substituents selected from the group consisting of            halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃            fluoroalkoxy and C₁₋₃ alkoxy; or        -   L is CH₂ and R3 is NH which is substituted with a 5-membered            heteroaryl which is optionally substituted with one or more            substituents selected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃            fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy;        -   R4 is pyridazinyl which can be optionally substituted one or            more times with one or more substituents selected from the            group consisting of halogen, cyano, C₁₋₄ alkyl, C₁₋₄            fluoroalkyl, C₁₋₄ deuterioalkyl, C₁₋₃ fluoroalkoxy,            cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6            wherein R5 and R6 are each independently selected from H,            C₁₋₃ alkyl and C₁₋₃ deuterioalkyl; or        -   R4 is 4-pyridinyl which can be optionally substituted one or            more times with one or more substituents selected from the            group consisting of halogen, cyano, C₁₋₄ alkyl, C₁₋₄            fluoroalkyl, C₁₋₄ deuterioalkyl, C₁₋₃ fluoroalkoxy,            cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6            wherein R5 and R6 are each independently selected from H,            C₁₋₃ alkyl and C₁₋₃ deuterioalkyl; or        -   R4 is a 9-membered bicyclic heteroaryl which can be            optionally substituted one or more times with one or more            substituents selected from the group consisting of halogen,            cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ deuterioalkyl,            C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃            deuterioalkoxy and —N—R5R6 wherein R5 and R6 are each            independently selected from H, C₁₋₃ alkyl and C₁₋₃            deuterioalkyl;-   or a pharmaceutically acceptable salt thereof.-   E2. A compound according to embodiment 1 of formula (Ia)

-   wherein-   L is selected from the group consisting of NH, CH₂, S and O;-   R1 is selected from the group consisting of hydrogen, linear or    branched C₁₋₅ alkyl, C₁₋₅ fluoroalkyl and saturated monocyclic C₃₋₅    cycloalkyl;-   R2 is selected from the group consisting of linear or branched C₁₋₈    alkyl, saturated monocyclic C₃₋₈ cycloalkyl, oxetanyl,    tetrahydrofuranyl, and tetrahydropyranyl; all of which can be    optionally substituted one or more times with one or more    substituents selected from the group consisting of methyl, fluorine,    hydroxy, cyano and methoxy;-   R3 is methyl substituted with a 9-membered bicyclic heteroaryl which    is optionally substituted with one or more substituents selected    from halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy    and C₁₋₃ alkoxy; or-   R3 is ethyl substituted with a 9-membered bicyclic heteroaryl which    is optionally substituted with one or more substituents selected    from halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy    and C₁₋₃ alkoxy; or-   L is CH₂ and R3 is NH which is substituted with a 9-membered    bicyclic heteroaryl which is optionally substituted with one or more    substituents selected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃    fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy;-   R4 is phenyl, pyridinyl, pyridazinyl or pyridonyl all of which can    be optionally substituted one or more times with one or more    substituents selected from the group consisting of halogen, cyano,    C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ deuterioalkyl, C₁₋₃ fluoroalkoxy,    cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6 wherein    R5 and R6 are each independently selected from H, C₁₋₃ alkyl and    C₁₋₃ deuterioalkyl; or-   R4 is a 5-membered heteroaryl which is optionally substituted with    one or more substituents selected from halogen, cyano, C₁₋₄ alkyl,    C₁₋₄ fluoroalkyl, C₁₋₄ deuterioalkyl, C₁₋₃ fluoroalkoxy,    cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6 wherein    R5 and R6 are each independently selected from H, C₁₋₃ alkyl and    C₁₋₃ deuterioalkyl; or-   R4 is a 4, 5 or 6 membered saturated heterocycle all of which can be    optionally substituted with one or more substituents selected from    oxo, C₁₋₄ alkyl and C₁₋₄ fluoroalkyl;-   or a pharmaceutically acceptable salt thereof.-   E3. The compound according to any of embodiments 1-2 wherein L is    NH.-   E4. The compound according to any of embodiments 1-3 wherein R1 is a    linear or branched C₁₋₃ alkyl.-   E5. The compound according to any of embodiments 1-4 wherein R1 is    methyl.-   E6. The compound according to any of embodiments 1-5 wherein R2 is a    linear or branched C₁₋₈ alkyl.-   E7. The compound according to any of embodiments 1-6 wherein R2 is a    linear or branched C₁₋₃ alkyl.-   E8. The compound according to embodiment 7 wherein R2 is isopropyl.-   E9. The compound according to any of embodiments 2-8 wherein R4 is    pyridinyl which is optionally substituted with ethoxy; or a    pharmaceutically acceptable salt thereof.-   E10. The compound according to any of embodiments 1-2 of formula    (laa)

-   wherein-   R1 is methyl;-   R2 is isopropyl;-   R3 is methyl substituted with a 9-membered bicyclic heteroaryl which    is optionally substituted with methyl;-   R4 is pyridinyl which is optionally substituted with ethoxy.-   E11. The compound according to any of embodiments 2-10 wherein said    9-membered bicyclic heteroaryl substituent in R3 is selected from    the group consisting of pyrazolo[1,5-a]pyridinyl,    imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl,    2,1,3-benzothiadiazolyl, imidazo[1,5-a]pyridinyl,    imidazo[1,2-a]pyridinyl, 1,3-benzoxazolyl and    [1,2,4]triazolo[1,5-a]pyridinyl.-   E12. The compound according to any of embodiments 1-2, selected from    the group consisting of:    -   1a.        5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(3-methyl-[1,2,4]triazolo[4,3-c]pyridin-8-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   2a.        N-(2,1,3-benzothiadiazol-4-ylmethyl)-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;    -   3a.        5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-([1,2,4]triazolo[4,3-c]pyridin-8-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;    -   4a.        5-(2-ethoxy-3-pyridyl)-N-(imidazo[1,2-c]pyridin-8-ylmethyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;    -   5a.        5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrazolo[1,5-c]pyridin-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;    -   6a.        5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-([1,2,4]triazolo[1,5-c]pyridin-5-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;    -   7a.        5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-[1,2,4]triazolo[1,5-c]pyridin-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   8a.        5-(2-ethoxy-3-pyridyl)-N-(imidazo[1,5-c]pyridin-8-ylmethyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;    -   9a.        N-(1,3-benzoxazol-7-ylmethyl)-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;    -   10a.        N-(1,3-benzoxazol-4-ylmethyl)-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;    -   11a.        5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-1,3-benzoxazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   12a.        5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-1,3-benzoxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   13a.        N-(1,3-benzoxazol-4-ylmethyl)-5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;    -   14a.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(2-methyl-1,3-benzoxazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   15a.        N-([1,2,4]triazolo[4,3-c]pyrimidin-5-ylmethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;    -   16a.        5-(2-ethoxypyridin-3-yl)-N-(imidazo[1,2-c]pyrimidin-5-ylmethyl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;-   or a pharmaceutically acceptable salt of any of these compounds.-   E13. A compound according to embodiment 1 of formula (Ib)

-   L is selected from the group consisting of NH, CH₂, S and O;-   R1 is selected from the group consisting of hydrogen, linear or    branched C₁₋₅ alkyl, C₁₋₅ fluoroalkyl and saturated monocyclic C₃₋₅    cycloalkyl;-   R2 is selected from the group consisting of linear or branched C₁₋₈    alkyl, saturated monocyclic C₃₋₈ cycloalkyl, oxetanyl,    tetrahydrofuranyl, and tetrahydropyranyl; all of which can be    optionally substituted one or more times with one or more    substituents selected from the group consisting of methyl, fluorine,    hydroxy, cyano and methoxy;-   R3 is methyl substituted with phenyl, pyridonyl, pyridinyl,    pyrimidinyl or pyrazinyl all of which can be optionally substituted    one or more times with one or more substituents selected from the    group consisting of halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl,    C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or-   R3 is methyl substituted with a 5-membered heteroaryl which is    optionally substituted with one or more substituents selected from    halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and    C₁₋₃ alkoxy; or-   R3 is ethyl substituted with phenyl, pyridonyl, pyridinyl,    pyrimidinyl or pyrazinyl all of which can be optionally substituted    one or more times with one or more substituents selected from the    group consisting of halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl,    C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or-   R3 is ethyl substituted with a 5-membered heteroaryl which is    optionally substituted with one or more substituents selected from    halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and    C₁₋₃ alkoxy; or-   L is CH₂ and R3 is NH which is substituted with phenyl, pyridonyl,    pyridinyl, pyrimidinyl or pyrazinyl all of which can be optionally    substituted one or more times with one or more substituents selected    from the group consisting of halogen, cyano, C₁₋₃ alkyl, C₁₋₃    fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or-   L is CH₂ and R3 is NH which is substituted with a 5-membered    heteroaryl which is optionally substituted with one or more    substituents selected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃    fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy;-   R4 is pyridazinyl which can be optionally substituted one or more    times with one or more substituents selected from the group    consisting of halogen, cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄    deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃    deuterioalkoxy and —N—R5R6 wherein R5 and R6 are each independently    selected from H, C₁₋₃ alkyl and C₁₋₃ deuterioalkyl; or-   R4 is 4-pyridinyl which can be optionally substituted one or more    times with one or more substituents selected from the group    consisting of halogen, cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄    deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃    deuterioalkoxy and —N—R5R6 wherein R5 and R6 are each independently    selected from H, C₁₋₃ alkyl and C₁₋₃ deuterioalkyl; or-   R4 is a 9-membered bicyclic heteroaryl which can be optionally    substituted one or more times with one or more substituents selected    from the group consisting of halogen, cyano, C₁₋₄ alkyl, C₁₋₄    fluoroalkyl, C₁₋₄ deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy,    C₁₋₃ alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6 wherein R5 and R6 are    each independently selected from H, C₁₋₃ alkyl and C₁₋₃    deuterioalkyl;-   or a pharmaceutically acceptable salt thereof.-   E14. The compound according to embodiment 13, wherein L is NH.-   E15. The compound according to anyone of embodiments 13-14, wherein    R1 is methyl.-   E16. The compound according to anyone of embodiments 13-15, wherein    R2 is selected from the group consisting of linear or branched C₁₋₈    alkyl, saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl,    tetrahydrofuranyl and tetrahydropyranyl, all of which are    unsubstituted.-   E17. The compound according to embodiment 16, wherein R2 is an    unsubstituted linear or branched C₁₋₄ alkyl.-   E18. The compound according to any of embodiments 13-17 wherein R3    is methyl substituted with phenyl, pyridonyl, pyridinyl, pyrimidinyl    or pyrazinyl all of which can be optionally substituted one or more    times with one or more substituents selected from the group    consisting of fluorine, C₁₋₃ alkyl and C₁₋₃ alkoxy.-   E19. The compound according to any of embodiments 13-17 wherein R3    is methyl substituted with phenyl, pyridonyl, pyridinyl, pyrimidinyl    or pyrazinyl all of which can be optionally substituted one or more    times with one or more substituents selected from the group    consisting of fluorine, methyl and methoxy.-   E20. The compound according to any of embodiments 13-17 wherein R3    is methyl substituted with a 5-membered heteroaryl which is    optionally substituted with one or more substituents selected from    the group consisting of fluorine, C₁₋₃ alkyl and C₁₋₃ alkoxy.-   E21. The compound according to any of embodiments 13-17 wherein R3    is methyl substituted with a 5-membered heteroaryl which is    optionally substituted one or more times with one or more    substituents selected from the group consisting of fluorine, methyl    and methoxy.-   E22. The compound according to any of embodiments 20-21, wherein    said 5-membered heteroaryl is selected from thiazolyl, oxazolyl,    isoxazolyl, triazolyl, pyrazolyl, tetrazolyl, imidazolyl,    oxadiazolyl and thiadiazolyl and thiophenyl.-   E23. The compound according to any of embodiments 13-22, wherein R4    is pyridazinyl which can be optionally substituted one or more times    with one or more substituents selected from the group consisting of    halogen, cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ deuterioalkyl,    C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃ deuterioalkoxy    and —N—R5R6 wherein R5 and R6 are each independently selected from    H, C₁₋₃ alkyl and C₁₋₃ deuterioalkyl.-   E24. The compound according to any of embodiments 13-22, wherein R4    is pyridazinyl which is substituted once with a C₁₋₃ alkoxy.-   E25. The compound according to embodiment 24, wherein said C₁₋₃    alkoxy is located at the 2-position of said pyridazinyl.-   E26. The compound according to any of embodiments 13-22, wherein R4    is 4-pyridinyl which can be optionally substituted one or more times    with one or more substituents selected from the group consisting of    halogen, cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ deuterioalkyl,    C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃ deuterioalkoxy    and —N—R5R6 wherein R5 and R6 are each independently selected from    H, C₁₋₃ alkyl and C₁₋₃ deuterioalkyl.-   E27. The compound according to any of embodiments 13-22, wherein R4    is 4-pyridinyl which is substituted once with a C₁₋₃ alkoxy.-   E28. The compound according to embodiment 27, wherein said C₁₋₃    alkoxy is located at the 2-position of said 4-pyridinyl.-   E29. The compound according to any of embodiments 13-22, wherein R4    is a 9-membered bicyclic heteroaryl which can be optionally    substituted one or more times with one or more substituents selected    from the group consisting of halogen, cyano, C₁₋₄ alkyl, C₁₋₄    fluoroalkyl, C₁₋₄ deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy,    C₁₋₃ alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6 wherein R5 and R6 are    each independently selected from H, C₁₋₃ alkyl and C₁₋₃    deuterioalkyl.-   E30. The compound according to any of embodiments 13-22, wherein R4    is a 9-membered bicyclic heteroaryl which can be optionally    substituted once with a methyl.-   E31. The compound according to any of embodiments 1 and 13 of    formula(Ibb)

-   wherein-   R1 is methyl;-   R2 is linear or branched C₁₋₈ alkyl;-   R3 is methyl substituted with phenyl, pyridonyl, pyridinyl,    pyrimidinyl or pyrazinyl all of which can be optionally substituted    one or more times with one or more substituents selected from the    group consisting of fluorine, C₁₋₃ alkyl and C₁₋₃ alkoxy; or-   R3 is methyl substituted with a 5-membered heteroaryl which is    optionally substituted with one or more substituents selected from    the group consisting of fluorine, C₁₋₃ alkyl and C₁₋₃ alkoxy;-   R4 is pyridazinyl which can be optionally substituted once with a    C₁₋₃ alkoxy; or-   R4 is 4-pyridinyl which can be optionally substituted once with a    C₁₋₃ alkoxy; or-   R4 is is a 9-membered bicyclic heteroaryl which can be optionally    substituted once with a methyl;-   or a pharmaceutically acceptable salt thereof.-   E32. The compound according to any of embodiments 13 and 29-31,    wherein said 9-membered bicyclic heteroaryl is selected from the    group consisting of indazolyl, indolyl and benzoxazolyl.-   E33. The compound according to any of embodiments 1 and 13, wherein    the compound is selected from the group consisting of    -   1b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-(pyrimidin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;    -   2b.        1-isopropyl-5-(3-methoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   3b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   4b.        1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(3-propoxypyridazin-4-yl)pyrazolo[4,3-b]pyridin-7-amine;    -   5b.        5-(3-ethoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,        enantiomer 1;    -   6b.        5-(3-ethoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,        enantiomer 2;    -   7b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;    -   8b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   9b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   10b.        5-(3-ethoxypyridazin-4-yl)-N-[(5-fluoropyrimidin-2-yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;    -   11b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(4-methylpyrimidin-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   12b.        5-(3-ethoxy-4-pyridyl)-N-[(6-fluoro-2-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;    -   13b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-(1H-pyrazol-3-ylmethyppyrazolo[4,3-b]pyridin-7-amine;    -   14b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine;    -   15b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine;    -   16b.        5-(3-ethoxypyridazin-4-yl)-N-[(2-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;    -   17b.        5-(3-ethoxy-4-pyridyl)-N-[(2-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;    -   18b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   19b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   20b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   21b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-a        mine;    -   22b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   23b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   24b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;    -   25b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-3-methylpyrazolo[4,3-b]pyridin-7-amine;    -   26b.        5-(3-ethoxypyridazin-4-yl)-N-[(6-fluoro-2-pyridyl)methyl]-1-isopropyl-3-methylpyrazolo[4,3-b]pyridin-7-a        mine;    -   27b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   28b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   29b.        1-isopropyl-5-(3-methoxy-4-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   30b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methylpyrazolo[4,3-b]pyridin-7-amine;    -   31b.        1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(3-propoxy-4-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;    -   32b.        5-(3-ethoxy-4-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,        enantiomer 1;    -   34b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   35b.        1-isopropyl-3-methyl-5-(2-methyl-1,3-benzoxazol-4-yl)-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   36b.        1-isopropyl-3-methyl-5-(2-methyl-1,3-benzoxazol-7-yl)-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   37b.        5-(1,3-benzoxazol-7-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   38b.        5-(1H-indol-7-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   39b.        5-(1H-indazol-7-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine:-   or a pharmaceutically acceptable salt of any of these compounds.-   10. The compound according to any of embodiments 1 and 13, wherein    the compound is selected from the group consisting of:    -   1b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-(pyrimidin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;    -   2b.        1-isopropyl-5-(3-methoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   3b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   4b.        1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(3-propoxypyridazin-4-yl)pyrazolo[4,3-b]pyridin-7-amine;    -   5b.        (R)-5-(3-ethoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine        or        (S)-5-(3-ethoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;    -   6b.        (R)-5-(3-ethoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine        or        (S)-5-(3-ethoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;    -   7b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methylpyrazolo[4,3-b]pyridin-7-amine;    -   8b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   9b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   10b.        5-(3-ethoxypyridazin-4-yl)-N-[(5-fluoropyrimidin-2-yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;    -   11b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(4-methylpyrimidin-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   12b.        5-(3-ethoxy-4-pyridyl)-N-[(6-fluoro-2-pyridyl)methyl]-1-isopropyl-3-methylpyrazolo[4,3-b]pyridin-7-amine;    -   13b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-(1H-pyrazol-3-ylmethyppyrazolo[4,3-b]pyridin-7-amine;    -   14b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine;    -   15b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine;    -   16b.        5-(3-ethoxypyridazin-4-yl)-N-[(2-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methylpyrazolo[4,3-b]pyridin-7-amine;    -   17b.        5-(3-ethoxy-4-pyridyl)-N-[(2-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methylpyrazolo[4,3-b]pyridin-7-amine;    -   18b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   19b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   20b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   21b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   22b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   23b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   24b.        5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-3-methylpyrazolo[4,3-b]pyridin-7-amine;    -   25b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-3-methylpyrazolo[4,3-b]pyridin-7-amine;    -   26b.        5-(3-ethoxypyridazin-4-yl)-N-[(6-fluoro-2-pyridyl)methyl]-1-isopropyl-3-methylpyrazolo[4,3-b]pyridin-7-amine;    -   27b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   28b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   29b.        1-isopropyl-5-(3-methoxy-4-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   30b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methylpyrazolo[4,3-b]pyridin-7-amine;    -   31b.        1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(3-propoxy-4-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;    -   32b.        (R)-5-(3-ethoxy-4-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine        or        (S)-5-(3-ethoxy-4-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;    -   34b.        5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   35b.        1-isopropyl-3-methyl-5-(2-methyl-1,3-benzoxazol-4-yl)-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   36b.        1-isopropyl-3-methyl-5-(2-methyl-1,3-benzoxazol-7-yl)-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   37b.        5-(1,3-benzoxazol-7-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   38b.        5-(1H-indol-7-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;    -   39b.        5-(1H-indazol-7-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine:-   or a pharmaceutically acceptable salt of any of these compounds.-   E35. A compound of any one of embodiments 1-34 or a pharmaceutically    acceptable salt thereof, for use in therapy.-   E36. A compound according to any of embodiments 1-34 or a    pharmaceutically acceptable salt thereof, for use as a medicament.-   E37. A pharmaceutical composition comprising a therapeutically    effective amount of a compound of any one of embodiments 1-34 or a    pharmaceutically acceptable salt thereof, and one or more    pharmaceutically acceptable carriers, diluents and/or excipients.-   E38. The pharmaceutical composition according to embodiment 37 for    use in the treatment of a neurodegenerative disorder, selected from    the group consisting of Alzheimer's Disease, Parkinson's Disease and    Huntington's Disease or for use in the treatment of a psychiatric    disorder such as Attention Deficit Hyperactivity Disorder (ADHD),    depression, anxiety, narcolepsy, cognitive impairment and cognitive    impairment associated with schizophrenia (CTAS), or another brain    disease like restless leg syndrome.-   E39. The pharmaceutical composition according to embodiment 38,    wherein said pharmaceutical composition further comprises a second    compound, which compound is selected from a compound useful in    active or passive Tau immunotherapy, a compound useful in active or    passive AB peptide immunotherapy, an NMDA receptor antagonist, an    acetylcholine esterase inhibitor, a BACE inhibitor, a 5-HT6 receptor    antagonist, an antiepileptic, an anti-inflammatory drug or an    anti-N3-pGlu Abeta monoclonal antibody.-   E40. The pharmaceutical composition according to embodiment 39,    wherein said composition is for use in the treatment of a    neurodegenerative disorder selected from the group consisting of    Alzheimer's Disease, Parkinson's Disease and Huntington's Disease.-   E41. The pharmaceutical composition according to embodiment 37,    further comprising a second compound, which compound is useful in    the treatment of a psychiatric disorder.-   E42. The pharmaceutical composition according to embodiment 41,    wherein said second compound has a pharmacological activity selected    from one or more of the following mechanisms: antagonist/inverse    agonist/negative modulator/partial agonist/inhibitor of one or more    of the targets dopamine D1 receptor, dopamine D2 receptor, dopamine    D3 receptor, phosphodiesterase PDE10, serotonin 5-HT2A receptor,    serotonin 5-HT6 receptor, and glycine transporter GlyT1; or    agonist/positive modulator/partial agonist of one or more of the    targets KCNQ channels, NMDA receptor, AMPA receptor and nicotinic    alpha-7 receptor.-   E43. The pharmaceutical composition according to embodiment 41,    wherein said second compound is selected from the list comprising    clozapine, risperidone, paliperidone, olanzapine, quetiapine,    amisulpride, ziprasidone, aripiprazole, brexpiprazole, asenapine,    haloperidole, iloperidone, lurasidone, chlorpromazine, blonanserin,    perphenazine, levomepromazine, sulpiride, fluphenazine,    zuclopenthixol, flupenthixol and cariprazine.-   E44. The pharmaceutical composition according to any of embodiments    41-44, wherein said composition is for use in the treatment of a    psychiatric disorder such as Attention Deficit Hyperactivity    Disorder (ADHD), depression, anxiety, narcolepsy, cognitive    impairment and cognitive impairment associated with schizophrenia    (CTAS).-   E45. A compound according to any of embodiments 1-34 or a    pharmaceutically acceptable salt thereof, for use in the treatment    of a neurodegenerative disorder, selected from the group consisting    of Alzheimer's Disease, Parkinson's Disease and Huntington's Disease    or for use in the treatment of a psychiatric disorder such as    Attention Deficit Hyperactivity Disorder (ADHD), depression,    anxiety, narcolepsy, cognitive impairment and cognitive impairment    associated with schizophrenia (CIAS), or another brain disease like    restless leg syndrome.-   E46. The compound according to any of embodiments 1-34 or a    pharmaceutically acceptable salt thereof, for use in the treatment    of a neurodegenerative disorder selected from the group consisting    of Alzheimer's Disease, Parkinson's Disease and Huntington's    Disease, wherein said compound is used in combination with a second    compound, which compound is selected from a compound useful in    active or passive Tau immunotherapy, a compound useful in active or    passive AB peptide immunotherapy, an NMDA receptor antagonist, an    acetylcholine esterase inhibitor, a BACE inhibitor, a 5-HT6 receptor    antagonist, an antiepileptic, an anti-inflammatory drug or an    anti-N3-pGlu Abeta monoclonal antibody.-   E47. The compound according to any of embodiments 1-34 or a    pharmaceutically acceptable salt thereof, for the use in the    treatment of a psychiatric disorder such as Attention Deficit    Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,    cognitive impairment and cognitive impairment associated with    schizophrenia (CIAS), wherein said compound is used in combination    with a second compound, which compound is useful in the treatment of    a psychiatric disorder.-   E48. The compound or pharmaceutically acceptable salt thereof for    the use according to embodiment 47, wherein said second compound,    which compound is useful in the treatment of a psychiatric disorder,    has a pharmacological activity selected from one or more of the    following mechanisms: antagonist/inverse agonist/negative    modulator/partial agonist/inhibitor of one or more of the targets    dopamine D1 receptor, dopamine D2 receptor, dopamine D3 receptor,    phosphodiesterase PDE10, serotonin 5-HT2A receptor, serotonin 5-HT6    receptor, and glycine transporter GlyT1; or agonist/positive    modulator/partial agonist of one or more of the targets KCNQ    channels, NMDA receptor, AMPA receptor and nicotinic alpha-7    receptor.-   E49. The compound or pharmaceutically acceptable salt thereof for    the use according to embodiment 47, wherein said second compound,    which compound is useful in the treatment of a psychiatric disorder,    is selected from the list comprising clozapine, risperidone,    paliperidone, olanzapine, quetiapine, amisulpride, ziprasidone,    aripiprazole, brexpiprazole, asenapine, haloperidole, iloperidone,    lurasidone, chlorpromazine, blonanserin, perphenazine,    levomepromazine, sulpiride, fluphenazine, zuclopenthixol,    flupenthixol and cariprazine.-   E50. A method for the treatment of a neurodegenerative disorder,    selected from the group consisting of Alzheimer's Disease,    Parkinson's Disease and Huntington's Disease or for the treatment of    a psychiatric disorder such as Attention Deficit Hyperactivity    Disorder (ADHD), depression, anxiety, narcolepsy, cognitive    impairment and cognitive impairment associated with schizophrenia    (CTAS), or another brain disease like restless leg syndrome, which    method comprises the administration of a therapeutically effective    amount of a compound according to any of embodiments 1-34 or a    pharmaceutically acceptable salt thereof, to a patient in need    thereof.-   E51. A method for the treatment of a neurodegenerative disorder,    selected from the group consisting of Alzheimer's Disease,    Parkinson's Disease and Huntington's Disease, which method comprises    the administration of a therapeutically effective amount of a    compound according to any of embodiments 1-34 or a pharmaceutically    acceptable salt thereof, in combination with a therapeutically    effective amount of a second compound, which compound is selected    from a compound useful in active or passive Tau immunotherapy, a    compound useful in active or passive AB peptide immunotherapy, an    NMDA receptor antagonist, an acetylcholine esterase inhibitor, a    BACE inhibitor, a 5-HT6 receptor antagonist, an antiepileptic, an    anti-inflammatory drug or an anti-N3-pGlu Abeta monoclonal antibody;    to a patient in need thereof.-   E52. A method for the treatment of a psychiatric disorder such as    Attention Deficit Hyperactivity Disorder (ADHD), depression,    anxiety, narcolepsy, cognitive impairment and cognitive impairment    associated with schizophrenia (CIAS), which method comprises the    administration of a therapeutically effective amount of a compound    according to any of embodiments 1-34 or a pharmaceutically    acceptable salt thereof, in combination with a therapeutically    effective amount of a second compound, which compound is useful in    the treatment of a psychiatric disorder; to a patient in need    thereof.-   E53. The method according to embodiment 52, wherein said second    compound, which compound is useful in the treatment of a psychiatric    disorder, has a pharmacological activity selected from one or more    of the following mechanisms: antagonist/inverse agonist/negative    modulator/partial agonist/inhibitor of one or more of the targets    dopamine D1 receptor, dopamine D2 receptor, dopamine D3 receptor,    phosphodiesterase PDE10, serotonin 5-HT2A receptor, serotonin 5-HT6    receptor, and glycine transporter GlyT1; or agonist/positive    modulator/partial agonist of one or more of the targets KCNQ    channels, NMDA receptor, AMPA receptor and nicotinic alpha-7    receptor.-   E54. The method according to embodiment 52, wherein said second    compound, which compound is useful in the treatment of a psychiatric    disorder, is selected from the list comprising clozapine,    risperidone, paliperidone, olanzapine, quetiapine, amisulpride,    ziprasidone, aripiprazole, brexpiprazole, asenapine, haloperidole,    iloperidone, lurasidone, chlorpromazine, blonanserin, perphenazine,    levomepromazine, sulpiride, fluphenazine, zuclopenthixol,    flupenthixol and cariprazine.-   E55. Use of a compound according to any of embodiments 1-34 or a    pharmaceutically acceptable salt thereof, in the manufacture of a    medicament for the treatment of a neurodegenerative disorder,    selected from the group consisting of Alzheimer's Disease,    Parkinson's Disease and Huntington's Disease or for the treatment of    a psychiatric disorder such as Attention Deficit Hyperactivity    Disorder (ADHD), depression, anxiety, narcolepsy, cognitive    impairment and cognitive impairment associated with schizophrenia    (CIAS), or another brain disease like restless leg syndrome.-   E56. Use of a compound according to any of embodiments 1-34 or a    pharmaceutically acceptable salt thereof, in the manufacture of a    medicament for the treatment of a neurodegenerative disorder,    selected from the group consisting of Alzheimer's Disease,    Parkinson's Disease and Huntington's Disease, wherein said    medicament is for use in combination with a second compound, which    compound is selected from a compound useful in active or passive Tau    immunotherapy, a compound useful in active or passive AB peptide    immunotherapy, an NMDA receptor antagonist, an acetylcholine    esterase inhibitor, a BACE inhibitor, a 5-HT6 receptor antagonist,    an antiepileptic, an anti-inflammatory drug or an anti-N3-pGlu Abeta    monoclonal antibody.-   E57. Use of a compound according to any of embodiments 1-34 or a    pharmaceutically acceptable salt thereof, in the manufacture of a    medicament for the treatment of a psychiatric disorder such as    Attention Deficit Hyperactivity Disorder (ADHD), depression,    anxiety, narcolepsy, cognitive impairment and cognitive impairment    associated with schizophrenia (CIAS), wherein said medicament is for    use in combination with a second compound, which compound is useful    in the treatment of a psychiatric disorder.-   E58. The use according to embodiment 57, wherein said second    compound, which compound is useful in the treatment of a psychiatric    disorder, has a pharmacological activity selected from one or more    of the following mechanisms: antagonist/inverse agonist/negative    modulator/partial agonist/inhibitor of one or more of the targets    dopamine D1 receptor, dopamine D2 receptor, dopamine D3 receptor,    phosphodiesterase PDE10, serotonin 5-HT2A receptor, serotonin 5-HT6    receptor, and glycine transporter GlyT1; or agonist/positive    modulator/partial agonist of one or more of the targets KCNQ    channels, NMDA receptor, AMPA receptor and nicotinic alpha-7    receptor.-   E59. The use according to embodiment 57, wherein said second    compound, which compound is useful in the treatment of a psychiatric    disorder, is selected from the list comprising clozapine,    risperidone, paliperidone, olanzapine, quetiapine, amisulpride,    ziprasidone, aripiprazole, brexpiprazole, asenapine, haloperidole,    iloperidone, lurasidone, chlorpromazine, blonanserin, perphenazine,    levomepromazine, sulpiride, fluphenazine, zuclopenthixol,    flupenthixol and cariprazine.

All references, including publications, patent applications and patents,cited herein are hereby incorporated by reference in their entirety andto the same extent as if each reference were individually andspecifically indicated to be incorporated by reference and were setforth in its entirety (to the maximum extent permitted by law).

Headings and sub-headings are used herein for convenience only, andshould not be construed as limiting the invention in any way.

The use of any and all examples, or exemplary language (including “forinstance”, “for example”, “e.g.”, and “as such”) in the presentspecification is intended merely to better illuminate the invention, anddoes not pose a limitation on the scope of invention unless otherwiseindicated.

The citation and incorporation of patent documents herein is done forconvenience only, and does not reflect any view of the validity,patentability and/or enforceability of such patent documents.

The present invention includes all modifications and equivalents of thesubject-matter recited in the claims appended hereto, as permitted byapplicable law.

Compounds of the Invention

TABLE 1 Compounds of the invention PDE1A, PDE1B, PDE1C, IC₅₀ IC₅₀ IC₅₀Example Compound (nM) (nM) (nM)  1a5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(3- 3 0.29 6.1methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine  2aN-(2,1,3-benzothiadiazol-4-ylmethyl)-5-(2-ethoxy- 53 3.4 1403-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3- b]pyridin-7-amine  3a5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 4.7 0.32 16([1,2,4]triazolo[4,3-a]pyridin-8-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine  4a5-(2-ethoxy-3-pyridyl)-N-(imidazo[1,2-a]pyridin-8- 6.6 0.48 22ylmethyl)-1-isopropyl-3-methyl-pyrazolo[4,3- b]pyridin-7-amine  5a5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 53 7.1 95(pyrazolo[1,5-a]pyridin-4-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine  6a5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N- 18 1.4 64([1,2,4]triazolo[1,5-a]pyridin-5-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine  7a5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2- 11 0.93 35methyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine  8a5-(2-ethoxy-3-pyridyl)-N-(imidazo[1,5-a]pyridin-8- 3.2 0.18 9.1ylmethyl)-1-isopropyl-3-methyl-pyrazolo[4,3- b]pyridin-7-amine  9aN-(1,3-benzoxazol-7-ylmethyl)-5-(2-ethoxy-3- 45 5.3 82pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3- b]pyridin-7-amine 10aN-(1,3-benzoxazol-4-ylmethyl)-5-(2-ethoxy-3- 14 0.94 39pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3- b]pyridin-7-amine 11a5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2- 18 4 26methyl-1,3-benzoxazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 12a5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2- 8.7 0.81 31methyl-1,3-benzoxazol-5-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 13aN-(1,3-benzoxazol-4-ylmethyl)-5-(3- 39 1.7 93ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine 14a5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3- 9.3 0.21 25methyl-N-[(2-methyl-1,3-benzoxazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine 15aN-([1,2,4]triazolo[4,3-c]pyrimidin-5-ylmethyl)- 30 4.8 435-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine 16a5-(2-ethoxypyridin-3-yl)-N-(imidazo[1,2- 35 4.0 44c]pyrimidin-5-ylmethyl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine 1b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl- 11 1.3 48N-(pyrimidin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7- amine 2b1-isopropyl-5-(3-methoxypyridazin-4-yl)-3- 45 8.1 49methyl-N-[(1-methylpyrazol-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine3b 5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl- 6.1 1.1 27N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 4b1-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 3.2 0.35 18yl)methyl]-5-(3-propoxypyridazin-4- yl)pyrazolo[4,3-b]pyridin-7-amine 5b5-(3-ethoxypyridazin-4-yl)-3-methyl-N-[(1- 25 6.1 102methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 1 6b5-(3-ethoxypyridazin-4-yl)-3-methyl-N-[(1- 1.9 0.36 11methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 7b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-[(2- 11 1.7 45methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 8b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl- 97 14 320N-[(5-methyl-1,3,4-oxadiazol-2- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine9b 5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl- 5.2 0.6 22N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 10b5-(3-ethoxypyridazin-4-yl)-N-[(5-fluoropyrimidin- 21 2.4 672-yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3- b]pyridin-7-amine 11b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl- 38 4.4 160N-[(4-methylpyrimidin-2-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 12b5-(3-ethoxy-4-pyridyl)-N-[(6-fluoro-2- 22 1.1 61pyridyl)methyl]-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 13b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N- 24 2.5 56(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7- amine 14b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl- 12 1.1 53N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7- amine 15b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-(2- 17 1.4 55pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine 16b5-(3-ethoxypyridazin-4-yl)-N-[(2-fluoro-3- 18 3.4 50pyridyl)methyl]-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 17b5-(3-ethoxy-4-pyridyl)-N-[(2-fluoro-3- 20 2.4 37pyridyl)methyl]-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 18b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl- 3.6 0.59 17N-[(1-methyl-1,2,4-triazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine19b 5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1- 11 0.91 22methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 20b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl- 5.7 1.1 24N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 21b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(2- 5.6 0.64 14methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin- 7-amine 22b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl- 4.6 0.4 15N-[(5-methyl-1H-pyrazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine 23b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(5- 5.5 0.55 12methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 24b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-[(6- 13 1.4 71methoxy-2-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 25b5-(3-ethoxy-4-pyridyl)-1-isopropyl-N-[(6-methoxy- 17 1.6 532-pyridyl)methyl]-3-methyl-pyrazolo[4,3- b]pyridin-7-amine 26b5-(3-ethoxypyridazin-4-yl)-N-[(6-fluoro-2- 6.5 1.2 44pyridyl)methyl]-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amine 27b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1- 17 1.6 42methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin- 7-amine 28b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1- 12 2.1 33methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin- 7-amine 29b1-isopropyl-5-(3-methoxy-4-pyridyl)-3-methyl-N- 32 4.9 44[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 30b5-(3-ethoxy-4-pyridyl)-1-isopropyl-N-[(2-methoxy- 27 2.7 653-pyridyl)methyl]-3-methyl-pyrazolo[4,3- b]pyridin-7-amine 31b1-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 4.6 0.38 18yl)methyl]-5-(3-propoxy-4-pyridyl)pyrazolo[4,3- b]pyridin-7-amine 32b5-(3-ethoxy-4-pyridyl)-3-methyl-N-[(1- 57 7.8 180methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 1 34b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(5- 49 7 130methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 35b1-isopropyl-3-methyl-5-(2-methyl-1,3-benzoxazol- 39 7.8 437-yl)-N-[(1-methylpyrazol-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine36b 1-isopropyl-3-methyl-5-(2-methyl-1,3-benzoxazol- 14 2.4 287-yl)-N-[(1-methylpyrazol-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine37b 5-(1,3-benzoxazol-7-yl)-1-isopropyl-3-methyl-N- 16 2.4 14[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine 38b5-(1H-indol-7-yl)-1-isopropyl-3-methyl-N-[(1- 590 100 350methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin- 7-amine 39b5-(1H-indazol-7-yl)-1-isopropyl-3-methyl-N-[(1- 140 24 300methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin- 7-amine

Table 1 lists the ICso value for inhibition of PDE1 by the compounds ofthe invention. The ICso value refers to the concentration (nM) of thecompound required to reach 50% inhibition of the PDE1 enzyme at thespecified substrate concentration. PDE1 assays are described in theExperimental Section.

SUPPORTING EXAMPLES

The compounds in Table 2 are disclosed herein in order to support thesubstituents R1, R2, R3, R4, R5 and R6.

TABLE 2 Supporting Examples PDE1A, PDE1B, PDE1C, Supporting IC₅₀ IC₅₀IC₅₀ example Compound (nM) (nM) (nM) S15-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 18 1.6 40N-[(5-methyl-1,3,4-oxadiazol-2- yl)methyl]pyrazolo[4,3-b]pyridin-7-amineS2 5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 0.46 0.071 4.9N-[(5-methylthiazol-2-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S35-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 0.8 0.11 3N-[(5-methylisoxazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine S45-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 8.6 0.86 19N-[(2-methyloxazol-5-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S55-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 11 1.8 28N-[(2-methyltriazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S65-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 4.8 0.22 5.6N-[(1-methyltriazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S75-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 21 1.1 37N-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine S85-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 2.9 0.34 8.9N-[(2-methyltetrazol-5- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine S95-(2-ethoxypyridin-3-yl)-1-isopropyl-3- 2.6 0.49 17methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine S105-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 4.1 0.47 14N-[(3-methylisoxazol-5- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine S115-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 9.6 0.72 30N-[(2-methylthiazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S121-cyclopropyl-5-(2-ethoxy-3-pyridyl)-3- 200 60 690methyl-N-[(1-methylpyrazol-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amineS13 5-(2-ethoxy-3-pyridyl)-N-[(1-methylpyrazol-4- 90 15 340yl)methyl]-1-propyl-pyrazolo[4,3-b]pyridin-7- amine S145-(2-ethoxypyridin-3-yl)-N-((1-methyl-1H- 450 38 300pyrazol-4-yl)methyl)-1-(oxetan-3-yl)-1H- pyrazolo[4,3-b]pyridin-7-amineS15 5-(2-ethoxypyridin-3-yl)-1-methyl-N-(1-(1- 820 200 36%methyl-1H-pyrazol-4-yl)ethyl)-1H- inhibitionpyrazolo[4,3-b]pyridin-7-amine (racemic) at 10 μM S165-(2-ethoxypyridin-3-yl)-1-methyl-N-((1- 670 92 1800methyl-1H-pyrazol-4-yl)methyl)-1H- pyrazolo[4,3-b]pyridin-7-amine S175-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1- 700 54 970methylimidazol-2-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S185-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1- 450 73 640methyl-1H-pyrazol-5-yl)methyl)-1H- pyrazolo[4,3-b]pyridin-7-amine S195-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1- 66 4.6 150methyl-1H-pyrazol-3-yl)methyl)-1H- pyrazolo[4,3-b]pyridin-7-amine S205-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(thiazol- 520 37 6002-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine S215-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1- 8.9 0.44 29methylimidazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S225-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(4- 250 50 430pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine S235-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(m- 240 38 750tolylmethyl)pyrazolo[4,3-b]pyridin-7-amine S245-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(p- 380 160 1200tolylmethyl)pyrazolo[4,3-b]pyridin-7-amine S255-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1- 56 4.6 150methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S265-(2-ethoxy-3-pyridyl)-1-ethyl-N-[(1- 140 22 440methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S275-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1- 94 6.6 170methylpyrazol-4-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine S285-(2-ethoxy-3-pyridyl)-1,3-dimethyl-N-[(1- 550 85 1900methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S295-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 27 1.1 44N-[(4-methylthiazol-2-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S305-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 15 1.3 31N-[(3-methyl-1,2,4-oxadiazol-5- yl)methyl]pyrazolo[4,3-b]pyridin-7-amineS31 5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 1.2 0.11 2.1N-[(1-methyl-1,2,4-triazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amineS32 5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 4.6 0.14 6.2N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S335-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 1.6 0.41 7.9N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine S345-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 8.1 1.8 21N-[(5-methyl-3-thienyl)methyl]pyrazolo[4,3- b]pyridin-7-amine S355-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 7.3 1.7 32N-[(4-methyl-2-thienyl)methyl]pyrazolo[4,3- b]pyridin-7-amine S365-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 24 5.2 41N-[(5-methyl-2-thienyl)methyl]pyrazolo[4,3- b]pyridin-7-amine S375-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 5.9 0.43 18N-[(2-methyloxazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S385-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 1.1 0.24 13N-[(5-methyloxazol-2-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S395-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 8.1 0.43 13N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine S405-(2-ethoxy-3-pyridyl)-N-(1H-imidazol-4- 14 1 32ylmethyl)-1-isopropyl-3-methyl-pyrazolo[4,3- b]pyridin-7-amine S41N-benzyl-5-(2-ethoxy-3-pyridyl)-1-isopropyl- 500 45 500pyrazolo[4,3-b]pyridin-7-amine S425-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3- 82 5.8 180methylisoxazol-5-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S435-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5- 30 2.4 80methyl-1,2,4-oxadiazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine S44N-[(1,5-dimethylpyrazol-3-yl)methyl]-5-(2- 19 1.4 70ethoxy-3-pyridyl)-1-isopropyl-pyrazolo[4,3- b]pyridin-7-amine S453-(1-isopropyl-3-methyl-7-(((1-methyl-1H- 8 0.62 16pyrazol-4-yl)methyl)amino)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpyridin-2(1H)-one S465-(2-ethoxypyridin-3-yl)-1-isopropyl-3- 5 0.42 9.7methyl-N-((2-methyl-1H-imidazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine S475-(2-ethoxypyridin-3-yl)-1-isopropyl-3- 1.6 0.069 1.8methyl-N-((5-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine S485-(2-ethoxypyridin-3-yl)-1-ethyl-3-methyl-N- 38 6.3 170((1-methyl-1H-pyrazol-4-yl)methyl)-1H- pyrazolo[4,3-b]pyridin-7-amineS49 3-(1-isopropyl-3-methyl-7-(((1-methyl-1H- 170 20 420pyrazol-4-yl)methyl)amino)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpyridin-2(1H)-one S505-(2-ethoxypyridin-3-yl)-1-isopropyl-3- 9 0.5 16methyl-N-((4-methyloxazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine 2,2,2- trifluoroacetate S51N-((1,2-dimethyl-1H-imidazol-4-yl)methyl)-5- 53 9.1 88(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine 2,2,2- trifluoroacetate S525-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 1.9 0.17 4.4N-[(5-methyl-1,2,4-oxadiazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amineS53 5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 9.3 0.89 17N-(1,2,4-oxadiazol-3-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine S54N-[(1,5-dimethylpyrazol-3-yl)methyl]-5-(2- 0.39 0.18 4.6ethoxy-3-pyridyl)-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amineS55 5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 3.4 0.51 5.5N-[(5-methyl-1H-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine S565-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1- 16 1 45methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S575-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(1H- 98 4.8 170pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7- amine S585-(2-ethoxypyridin-3-yl)-1-isopropyl-3- 1.1 0.17 2.1methyl-N-((1-methyl-1H-imidazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine 2,2,2-trifluoroacetate S595-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 55 12 120N-(1,3,4-oxadiazol-2-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine S605-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 6.5 0.59 12N-[(1-methylpyrazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine S615-(1,3-dimethylpyrazol-4-yl)-1-isopropyl-3- 550 120 680methyl-N-[(1-methylpyrazol-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amineS62 1-isopropyl-5-(2-methoxy-3-pyridyl)-3- 16 2.4 21methyl-N-[(1-methylpyrazol-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amineS63 1-isopropyl-5-(2-methoxyphenyl)-3-methyl-N- 64 9.4 20[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S641-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 52 12 47yl)methyl]-5-phenyl-pyrazolo[4,3-b]pyridin-7- amine S651-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 7.9 1.2 16yl)methyl]-5-(2-methyl-3- thienyl)pyrazolo[4,3-b]pyridin-7-amine S665-(1,5-dimethylpyrazol-4-yl)-1-isopropyl-3- 210 59 220methyl-N-[(1-methylpyrazol-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amineS67 5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 9.6 0.64 27methylpropyl]-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S683-methyl-1-[1-methylpropyl]-N-[(2- 0.79 0.14 1.3methyltetrazol-5-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S695-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N- 14 1.2 40[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine,enantiomer 1 S70 5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N- 140 14 360[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine,enantiomer 2 S71 5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4- 170 18 180methylthiazol-5-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S725-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3- 14 2.4 39methyl-pyrazolo[4,3-b]pyridin-7- yl]oxymethyl]-2-methyl-oxazole S735-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 81 9.2 140N-(pyrimidin-4-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine S745-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 2.1 0.34 8.1N-(pyrimidin-2-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine S755-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 9.9 0.81 33N-[(4-methylpyrimidin-2- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine S765-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 23 2.9 32N-(pyrazin-2-ylmethyl)pyrazolo[4,3-b]pyridin- 7-amine S775-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 21 0.22 64N-[[2-(trifluoromethyl)-3- pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine S78 4-[[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3- 27 3.2 44methyl-pyrazolo[4,3-b]pyridin-7- yl]amino]methyl]-1-methyl-pyridin-2-oneS79 5-(2-(ethylamino)pyridin-3-yl)-1-isopropyl-3- 230 31 260methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine S815-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4- 1 0.26 4.7methoxy-2-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S825-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6- 16 1 35methoxypyrazin-2-yl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S835-(2-ethoxy-3-pyridyl)-N-[(5-fluoropyrimidin- 17 1.2 382-yl)methyl]-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S845-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 19 1.8 23N-[(2-methyl-3-pyridyl)methyl]pyrazolo[4,3- b]pyridin-7-amine S855-(2-ethoxy-3-pyridyl)-N-[(2-fluoro-3- 8.4 0.22 27pyridyl)methyl]-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S865-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2- 20 0.36 68methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S875-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 6.3 0.95 13N-[(6-methyl-3-pyridyl)methyl]pyrazolo[4,3- b]pyridin-7-amine S885-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2- 110 5.1 170methoxyphenyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S895-(2-ethoxy-3-pyridyl)-N-[(2- 61 1.5 93fluorophenyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine S905-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 270 12 640 N-[[2-(trifluoromethyl)phenyl]methyl]pyrazolo[4,3- b]pyridin-7-amine S915-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3- 27 2.3 70methoxypyrazin-2-yl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S925-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4- 47 2.7 110methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S931-isopropyl-3-methyl-N-[(2-methyltetrazol-5- 4.3 0.96 17yl)methyl]-5-(2-propoxy-3- pyridyl)pyrazolo[4,3-b]pyridin-7-amine S941-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 1.4 0.065 4.9yl)methyl]-5-(2-propoxy-3- pyridyl)pyrazolo[4,3-b]pyridin-7-amine S951-isopropyl-5-(2-methoxy-3-pyridyl)-N-[(2- 42 6.4 28methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S961-isopropyl-5-(2-methoxy-3-pyridyl)-N-[(6- 18 3.8 5.3methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S975-(2-isopropoxy-3-pyridyl)-1-isopropyl-3- 1.4 0.6 9.1methyl-N-[(1-methylpyrazol-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amineS98 5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 7.2 0.58 21N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine S995-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 0.73 0.31 3.8N-(2H-tetrazol-5-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine S1005-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 6.3 0.39 21N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7- amine S1015-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 20 0.9 43N-[(6-methyl-2-pyridyl)methyl]pyrazolo[4,3- b]pyridin-7-amine S1025-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6- 8 0.73 34methoxy-2-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S1035-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 5.4 2.9 17N-[(2-methyl-4-pyridyl)methyl]pyrazolo[4,3- b]pyridin-7-amine S1045-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2- 2.2 0.16 6.3methoxy-4-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S1055-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 54 12 150N-[(2-methylpyrimidin-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine S1065-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5- 2.1 0.45 3.9methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S1075-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 110 5.6 170N-[[6-(trifluoromethyl)-2- pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine S108 3-[[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3- 2.8 0.36 12methyl-pyrazolo[4,3-b]pyridin-7- yl]amino]methyl]-1-methyl-pyridin-2-oneS109 5-(2-ethoxy-3-pyridyl)-N-[(1-ethylpyrazol-4- 4.9 0.66 11yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3- b]pyridin-7-amine S1105-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 11 1.1 8.5N-[(1-propylpyrazol-4-yl)methyl]pyrazolo[4,3- b]pyridin-7-amine S1115-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6- 28 1.4 68methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S1125-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5- 61 12 100methoxy-2-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S1135-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2- 110 5.7 130methylthiazol-4-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine S1145-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5- 24 3 46methoxypyrazin-2-yl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amineS115 5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 15 2 31N-(3-pyridylmethyl)pyrazolo[4,3-b]pyridin-7- amine S1165-(2-ethoxy-3-pyridyl)-N-[(6-fluoro-3- 21 2.4 46pyridyl)methyl]-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amineS117 N-[[6-(difluoromethyl)-3-pyridyl]methyl]-5-(2- 18 2.3 26ethoxy-3-pyridyl)-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amineS118 5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3- 13 0.42 88methoxy-2-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S1195-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 12 0.56 29methylpropyl]-N-(1H-pyrazol-3- ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 S120 5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 4.6 0.27 7.6methylpropyl]-N-(1H-pyrazol-3- ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 S121 5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 4 0.47 10methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 1 S1225-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 2.2 0.15 3.5methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S1235-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl- 54 7 1301,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 1 S1245-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl- 9.7 1.1 211,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S1255-(2-ethoxy-3-pyridyl)-N-[(5-methoxy-3- 1 0.32 4.3pyridyl)methyl]-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S1265-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4- 5.4 0.51 8.4pyridyl)methyl]-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S1275-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 1.8 0.31 5.1methylpropyl]-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S1285-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl- 1.2 0.26 4.11,2,4-oxadiazol-3-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S1295-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2- 11 1.2 25methyloxazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S1305-(2-ethoxy-3-pyridyl)-N-(1H-imidazol-4- 11 0.86 25ylmethyl)-3-methyl-1-[1- methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 S131 5-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 0.35 0.042 0.46methylpropyl]-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S1325-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1- 0.14 0.045 0.52methylimidazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S1335-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2- 11 1.3 23methyloxazol-5-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S1343-methyl-1-[1-methylpropyl]-N-[(1-methyl- 0.96 0.12 1.51,2,4-triazol-3-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S1353-methyl-1-[1-methylpropyl]-5-(2-propoxy-3- 1.9 0.095 3.6pyridyl)-N-(1H-pyrazol-3- ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 S136 5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N- 62 3.2100 (1H-pyrazol-3-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine, enantiomer 1S137 5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N- 180 12 340(1H-pyrazol-3-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine, enantiomer 2S138 5-(2-ethoxy-3-pyridyl)-N-[(5-methyl-1,3,4- 93 6.8 180oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 1 S1395-(2-ethoxy-3-pyridyl)-N-[(5-methyl-1,3,4- 330 35 530oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S1405-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N- 32 1.7 52[(1-methyl-1,2,4-triazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 S141 5-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N- 44 2.2 76[(1-methyl-1,2,4-triazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 S142 1-isopropyl-3-methyl-N-[(1-methylimidazol-4- 0.26 0.10.8 yl)methyl]-5-(2-propoxy-3- pyridyl)pyrazolo[4,3-b]pyridin-7-amineS143 1-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)- 3.8 0.26 9.2N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine S1445-(2-ethoxy-3-pyridyl)-3-methyl-1-[1- 14 1.1 23methylpropyl]-N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine, enantiomer 2 S1451-isopropyl-3-methyl-N-[(1-methyl-1,2,4- 0.41 0.095 1.2triazol-3-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine S1461-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)- 3.9 0.51 14N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine S1471-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 12 2.1 28yl)methyl]-5-thiazol-2-yl-pyrazolo[4,3- b]pyridin-7-amine S1481-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 110 58 86yl)methyl]-5-(5-methylthiazol-2- yl)pyrazolo[4,3-b]pyridin-7-amine S1491-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 29 2.4 69yl)methyl]-5-(4-methylthiazol-2- yl)pyrazolo[4,3-b]pyridin-7-amine S1503-[1-isopropyl-3-methyl-7-[(1-methylpyrazol- 44 33 134-yl)methylamino]pyrazolo[4,3-b]pyridin-5- yl]-5-methyl-oxazolidin-2-oneS151 3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol- 10 4.7 124-yl)methylamino]pyrazolo[4,3-b]pyridin-5- yl]oxazolidin-2-one S1521-[1-isopropyl-3-methyl-7-[(1-methylpyrazol- 48 32 614-yl)methylamino]pyrazolo[4,3-b]pyridin-5- yl]azetidin-2-one S1531-tert-butyl-3-[1-isopropyl-3-methyl-7-[(1- 130 76 270 methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5- yl]imidazolidin-2-one S1541-[1-isopropyl-3-methyl-7-[(1-methylpyrazol- 26 3.6 494-yl)methylamino]pyrazolo[4,3-b]pyridin-5- yl]pyrrolidin-2-one S1553-[1-isopropyl-3-methyl-7-[(1-methylpyrazol- 8.2 4.9 3.94-yl)methylamino]pyrazolo[4,3-b]pyridin-5- yl]-4-methyl-oxazolidin-2-oneS156 4-ethyl-3-[1-isopropyl-3-methyl-7-[(1- 31 31 5.1 methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5- yl]oxazolidin-2-one S157N-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3- 34 14 77methyl-pyrazolo[4,3-b]pyridin-7-yl]methyl]-5- methoxy-pyridin-3-amineS158 N-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3- 23 4.9 50methyl-pyrazolo[4,3-b]pyridin-7-yl]methyl]-1-methyl-1,2,4-triazol-3-amine S1595-(2-ethoxy-3-pyridyl)-1-isopropyl-7-[2-(5- 270 70 1600methoxy-3-pyridyl)ethyl]-3-methyl- pyrazolo[4,3-b]pyridine S1605-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 23 3.9 567-[2-(1-methyl-1,2,4-triazol-3- yl)ethyl]pyrazolo[4,3-b]pyridine S1615-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 60 6.6 120N-[(2-methyl-1,2,4-triazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amineS162 5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 100 13 180N-[(4-methyl-1,2,4-triazol-3- yl)methyl]pyrazolo[4,3-b]pyridin-7-amineS163 5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methyl- 120 14 1201,2,4-triazol-3-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine S1645-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl- 6.8 1.6 257-[(1-methylpyrazol-4- yl)methylsulfanyl]pyrazolo[4,3-b]pyridine S165N-[[1-(difluoromethyl)pyrazol-4-yl]methyl]-5- 73 5.9 110(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine S166 5-(2-ethoxy-3-pyridyl)-N-[[5- 2.10.16 7.2 (fluoromethyl)isoxazol-3-yl]methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7- amine S1675-(2-ethoxy-3-pyridyl)-N-[[3- 11 1 33(fluoromethyl)isoxazol-5-yl]methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7- amine S1681-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 14 2.6 36yl)methyl]-5-oxazol-2-yl-pyrazolo[4,3- b]pyridin-7-amine S1691-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 610 85 170yl)methyl]-5-(3-methyltriazol-4- yl)pyrazolo[4,3-b]pyridin-7-amine S1701-isopropyl-5-(2-methoxy-3-pyridyl)-3- 42 5.3 46methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7- amine S1713-[1-isopropyl-7-[(2-methoxy-3- 290 47 420pyridyl)methylamino]-3-methyl-pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one S1725-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3- 40 5.5 46methoxy-4-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amine S1731-isopropyl-5-(2-methoxy-3-pyridyl)-3- 49 6.3 26methyl-N-[(2-methylthiazol-5- yl)methyl]pyrazolo[4,3-b]pyridin-7-amineS174 5-(2-cyclopropoxypyridin-3-yl)-1-isopropyl-N- 18 1.5 52((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine S1751-isopropyl-N-((2-methoxypyridin-3- 83 17 130yl)methyl)-3-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine S1765-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5- 81 12 93methoxypyrimidin-2-yl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amineS177 3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol- 130 20 1804-yl)methylamino]pyrazolo[4,3-b]pyridin-5- yl]-1H-pyridin-2-one S178N-[[2-(difluoromethyl)-3-pyridyl]methyl]-5-(2- 31 3.2 63ethoxy-3-pyridyl)-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amineS179 5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6- 2.8 0.51 7methoxypyrimidin-4-yl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amineS180 5-(2-(ethoxy-1,1-d₂)pyridin-3-yl)-1-isopropyl- 27 0.77 78N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine S1815-(2-(ethoxy-d₅)pyridin-3-yl)-1-isopropyl-N- 31 1.6 84((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine S1825-(2-(ethoxy-2,2,2-d₃)pyridin-3-yl)-1- 24 1.1 61isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine S1831-isopropyl-N-((2-methoxypyridin-3- 290 38 350 yl)methyl)-3-methyl-5-(2-(trifluoromethyl)pyridin-3-yl)-1H- pyrazolo[4,3-b]pyridin-7-amine S1843-(difluoromethyl)-5-(2-ethoxypyridin-3-yl)-1- 13 2.4 45isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine S1851-isopropyl-3-methyl-N-((1-methyl-1H- 100 24 92pyrazol-4-yl)methyl)-5-(1H-1,2,4-triazol-1-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine S1863-[1-isopropyl-3-methyl-7-[(1-methyl-1,2,4- 64 15 130triazol-3-yl)methylamino]pyrazolo[4,3- b]pyridin-5-yl]-1H-pyridin-2-oneS187 3-[1-isopropyl-3-methyl-7-(1H-pyrazol-3- 140 18 250ylmethylamino)pyrazolo[4,3-b]pyridin-5-yl]- 1H-pyridin-2-one S1885-[2-(difluoromethoxy)-3-pyridyl]-1-isopropyl- 61 7.8 60N-[(2-methoxy-3-pyridyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amineS189 5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4- 3.9 0.49 19methoxypyrimidin-2-yl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amineS190 5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4- 74 7.9 94methoxypyrimidin-5-yl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amineS191 5-(2-ethoxy-3-pyridyl)-N-[(2-ethoxy-3- 160 10 400pyridyl)methyl]-1-isopropyl-3-methyl- pyrazolo[4,3-b]pyridin-7-amineS192 5-[2-(dimethylamino)-3-pyridyl]-1-isopropyl- 630 71 490N-[(4-methoxyphenyl)methyl]-3-methyl- pyrazolo[4,3-b]pyridin-7-amineS193 3-[1-isopropyl-3-methyl-7-[[2- 320 54 880 (trifluoromethyl)-3-pyridyl]methylamino]pyrazolo[4,3-b]pyridin- 5-yl]-1H-pyridin-2-one S1941-isopropyl-3-methyl-5-(3-methylisoxazol-4- 95 23 21yl)-N-[(1-methylpyrazol-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amine S1951-isopropyl-3-methyl-5-(1-methyl-1H-1,2,4- 420 110 160triazol-5-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine S1961-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)- 18 1.7 27N-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3- b]pyridin-7-amine S1975-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-3- 190 13 190pyridyl)methyl]-3-methyl-1-(oxetan-3- yl)pyrazolo[4,3-b]pyridin-7-amineS198 5-(2-(ethyl(methyl)amino)pyridin-3-yl)-1- 1100 240 1000isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine S1995-(2-ethoxypyridin-3-yl)-3-(fluoromethyl)-1- 7.4 0.75 26isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine S2001-isopropyl-3-methyl-N-((1-methyl-1H- 98 18 110pyrazol-4-yl)methyl)-5-(4-methyloxazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine S2015-[2-(dimethylamino)-3-pyridyl]-1-isopropyl- 2100 230 21003-methyl-N-[(1-methylpyrazol-4- yl)methyl]pyrazolo[4,3-b]pyridin-7-amineS202 1-isopropyl-3-methyl-N-((1-methyl-1H- 92 14 170pyrazol-4-yl)methyl)-5-(4-methyloxazol-2-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine S2031-isopropyl-3-methyl-N-[(1-methylpyrazol-4- 410 180 420yl)methyl]-5-(4-methyl-1,2,4-triazol-3-yl)pyrazolo[4,3-b]pyridin-7-amine

Table 2 lists the ICso value for inhibition of PDE1 by the supportingexamples. The ICso value refers to the concentration (nM) of thecompound required to reach 50% inhibition of the PDE1 enzyme at thespecified substrate concentration. PDE1 assays are described in theExperimental Section.

EXPERIMENTAL SECTION Preparation of the Compounds of theInvention—General Methods

The compounds of formula (I) may be prepared by methods described below,together with synthetic methods known in the art of organic chemistry,or modifications that are familiar to those of ordinary skill in theart. The starting materials used herein are available commercially ormay be prepared by routine methods known in the art, such as thosemethodS described in standard reference books such as “Compendium ofOrganic Synthetic Methods, Vol. I-XIII” (published withWiley-Interscience, ISSN: 1934-4783). Preferred methods include, but arenot limited to, those described below.

The schemes are representative of methods useful in synthesizing thecompounds of the present invention and the supporting examples. They arenot to constrain the scope of the invention in any way.

Method 1:

where R1 is as described for formula I and R is hydrogen or R is R₂ asdescribed for formula I. Compounds of general formula IV (Scheme 1) canbe prepared from compounds of general formula II and III.

Method 2:

where R1 is as described for formula I and R is R2 as described forformula I or a protection group such as para-methoxy benzyl.

Compounds of general formula IV (Scheme 2) can be prepared fromcompounds of general formula II, III and V as described in theliterature (e.g. Int. Pat. App. WO2013142307)

Method 3:

where R1 is as described for formula I, R is R2 as described for formulaI or R is a protection group such as para-methoxy benzyl and Y is ahalogen such as chlorine or bromine.

Compounds of general formula VIII (Scheme 3) can be prepared bynitration of compounds of general formula IV followed by reduction.Compounds of general formula XI can be prepared by reaction of compoundsof general formula VIII with methyl 3-chloro-3-oxopropanoate followed byring-closure in the presence of a base such as sodium ethoxide or sodiummethoxide. Hydrolysis and decarboxylation of compounds of generalformula XI followed by treatment with phosphoryl trichloride orphosphoryl tribromide gives compounds of general formula XIII.

Method 4:

where R1 and R2 are as described for formula I, R is a protection groupsuch as para-methoxy benzyl, Y is a halogen such as chlorine or bromineand Z is a leaving group such as chlorine, bromine, iodine or amethanesulfonate group or Z is a hydroxy group.

Compounds of general formula XIV (Scheme 4) can be prepared by thedeprotection of compounds of general formula XIII where R is aprotection group. If the protection group is para-methoxy benzyl, thedeprotection can be performed by treatment with an acid such astrifluoroacetic acid. Compounds of general formula XIII can be preparedby reaction of compounds of general formula XIV with compounds ofgeneral formula XV in the presence of a base such as cesium carbonate orusing Mitsunobu reaction conditions when Z is a hydroxy group.

Method 5:

where R1, R2, R3 and R4 are as described for formula I, L is NH, O or Sand R are hydroxy groups or R together with the boron atom form a4,4,5,5-tetramethyl-1,3,2-dioxaborolane group. Y is a halogen such aschlorine or bromine.

Compounds of general formula XVII (Scheme 5) can be prepared bytreatment of compounds of general formula XIII with compounds of generalformula XVI in the presence of a base such as but not limited to cesiumfluoride or N,N-diisopropylethylamine. Compounds of general formula Ican be prepared from compounds of general formulae XVII and XVIII in thepresence of a palladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and abase such as potasium carbonate or other Suzuki-Miyaura couplingreaction conditions known to chemists skilled in the art of organicsynthesis.

Method 6:

where R1, R2, R3 and R4 are as described for formula I, R are hydroxygroups or R together with the boron atom form a4,4,5,5-tetramethyl-1,3,2-dioxaborolane group and Pg is a protectiongroup such as para-methoxy benzyl. Y is a halogen such as chlorine orbromine.

Compounds of general formula XX (Scheme 6) can be prepared by treatmentof compounds of general formula XIII with compounds of general formulaXIX in the presence of a base such as but not limited to cesium fluorideor N,N-diisopropylethylamine. Compounds of general formula XXI can beprepared from compounds of general formulae XX and XVIII in the presenceof a palladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and abase such as potassium carbonate or other Suzuki-Miyaura couplingreaction conditions known to chemists skilled in the art of organicsynthesis. Compounds of general formula XXII can be prepared bydeprotection of compounds of general formula XXI. If the protectiongroup is para-methoxy benzyl, the deprotection can be performed bytreatment with an acid such as trifluoroacetic acid. Compounds ofgeneral formula I can be prepared by reductive amination of compounds ofgeneral formula XXII with the appropriate aldehyde or ketone.

Method 7:

where R1, R2, and R3 are as described for formula I, L is NH, O or S, Rare hydroxy groups or R together with the boron atom form a4,4,5,5-tetramethyl-1,3,2-dioxaborolane group. Y is a halogen such aschlorine or bromine.

Compounds of general formula XXIV (Scheme 7) can be prepared fromcompounds of general formulae XIII and XXIII in the presence of apalladium catalyst such as [1,140-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and a basesuch as potassium carbonate or other Suzuki-Miyaura coupling reactionconditions known to chemists skilled in the art of organic synthesis.Compounds of general formula XXV can be prepared by treatment ofcompounds of general formula XXIV with compounds of general formula XVIin the presence of a base such as but not limited to cesium fluoride orN,N-diisopropylethylamine. Compounds of general formula I can beprepared by treatment of compounds of general formula XXV with sodiumethoxide.

Method 8:

where R1, R2, R3, R4 and L are as described for formula I and M is ZnClor SnR₃, where R are alkyl groups such as butyl or methyl. Y is ahalogen such as chlorine or bromine.

Compounds of general formula I (Scheme 8) can be prepared from compoundsof general formulae XVII and XXVI in the presence of a palladiumcatalyst such Pd(PPh₃)₄ or other Stille or Negishi coupling reactionconditions known to chemists skilled in the art of organic synthesis.

Method 9:

where R1, R2, R3, and L are as described for formula I and M is ZnCl orSn(R)₃, where R are alkyl groups such as butyl or methyl. Y is a halogensuch as chlorine or bromine. R4 is as described for formula I with theattachment point of R4 is a nitrogen.

Compounds of general formula I (Scheme 9) can be prepared from compoundsof general formulae XVII and XXVII in the presence of a copper catalystsuch as CuI in combination with a ligand or palladium catalyst such asPd₂(dba)₃ in combination with Xantphos and a base such as Cs₂CO₃ usingreaction conditions known to chemists skilled in the art of organicsynthesis.

Method 10:

where R1, R2 and R4 are as described for formula I, L is CH₂ and

R3 is methyl substituted with phenyl, pyridonyl, pyridinyl, pyrimidinylor pyrazinyl all of which can be optionally substituted one or moretimes with one or more substituents selected from the group consistingof halogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxyand C₁-C₃ alkoxy; or R3 is methyl substituted with a 5-memberedheteroaryl which is optionally substituted with one or more substituentsselected from halogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃fluoroalkoxy and C₁-C₃ alkoxy. R5 is phenyl, pyridonyl, pyridinyl,pyrimidinyl or pyrazinyl all of which can be optionally substituted oneor more times with one or more substituents selected from the groupconsisting of halogen, cyano, C₁-C3 alkyl, C₁-C₃ fluoroalkyl, C₁-C₃fluoroalkoxy and C₁-C₃ alkoxy; or R5 is a 5-membered heteroaryl which isoptionally substituted with one or more substituents selected fromhalogen, cyano, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxy andC₁-C₃ alkoxy. Y is a halogen such as chlorine or bromine. X is a halogensuch as iodine or bromine.

Compounds of general formula XXVIII (Scheme 10) can be prepared bytreatment of compounds of general formula XIII with a reagent such asi-PrMgCl-LiCl followed by treatment with N,N-dimethyl formamide.Compounds of general formula XXIX can be prepared by treatment ofcompounds of general formula XXVIII with a reagent such as1-diazo-1-dimethoxyphosphoryl-propan-2-one and a base such as Cs₂CO₃.Compounds of general formula XXXI can be prepared from compounds ofgeneral formulae XXIX and XXX in the presence of a palladium catalystsuch as [1,1T-bis(diphenylphosphino)ferrocene]palladium(II) dichloride,a base such as triethylamine and a copper catalyst such as Cul usingreaction conditions known to chemists skilled in the art of organicsynthesis. Compounds of general formula I can be prepared by treatmentof compounds of general formula XXXI with palladium on carbon under anatmosphere of hydrogen.

Method 11:

where R1, R2 and R4 are as described for formula I,

L is CH₂ and R3 is NH which is substituted with phenyl, pyridonyl,pyridinyl, pyrimidinyl or pyrazinyl all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of halogen, cyano, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ fluoroalkoxy and C₁-C₃ alkoxy; or L is CH₂ and R3 isNH which is substituted with a 5-membered heteroaryl which is optionallysubstituted with one or more substituents selected from halogen, cyano,C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxy and C₁-C₃ alkoxy. R5is phenyl, pyridonyl, pyridinyl, pyrimidinyl or pyrazinyl all of whichcan be optionally substituted one or more times with one or moresubstituents selected from the group consisting of halogen, cyano, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ fluoroalkoxy and C₁-C₃ alkoxy; or R5 isa 5-membered heteroaryl which is optionally substituted with one or moresubstituents selected from halogen, cyano, C₁-C₃ alkyl, C₁-C₃fluoroalkyl, C₁-C₃ fluoroalkoxy and C₁-C₃ alkoxy. Y is a halogen such aschlorine or bromine.

Compounds of general formula XVII (Scheme 11) can be prepared byreductive amination of compounds of general formula XXVIII withcompounds of general formula XXXII.

Method 12:

where R1, R2, R3 and R4 are as described for formula I and L is sulphur.Y is a halogen such as chlorine or bromine. Pg is a protecting groupsuch as 6-methylheptyl propano-3-ate. Lg is a leaving group such aschlorine, bromine, iodine, 4-methylbenzenesulfonate or methanesulfonate.

Compounds of general formula XXXIII (Scheme 12) can be prepared bytreatment of compounds of general formula XIII with a reagent such as6-methylheptyl 3-mercaptopropanoate in the presence of a base such asdiisopropyl ethylamine. Compounds of general formula XXXIV can beprepared by the same methods as described in methods 5, 8 and 9.Compounds of general formula I can be prepared by deprotection ofcompounds of general formula XXXIV by using a base such as potassiumtert-butoxide followed by alkylation with compounds of general formulaXXXVI.

Method 13:

where R1, R2, R3 and R4 are as described for formula I and L is NH. Pgis a protecting group such as p-methoxybenzyl and Lg is a leaving groupsuch as chlorine, bromine, iodine, 4-methylbenzenesulfonate ormethanesulfonate.

Compounds of general formula XXXVII (Scheme 13) can be prepared bydeprotonation of compounds of general formula XXI with a base such assodium hydride followed by alkylation with compounds of general formulaXXXVI. Compounds of general formula I can be prepared by removal of theprotecting group (Pg) using reaction conditions known to chemistsskilled in the art of organic synthesis, e.g. by treatment withtrifluoroacetic acid when Pg is p-methoxybenzyl.

LC-MS Methods

Method A: An Agilent 1200 LCMS system with ELS detector was used.Phenomenex Luna-C18, 5 μm; 2.0×50 mm; Column temperature: 50° C.;Solvent system: A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=90:10 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method B: An Agilent 1200 LCMS system with ELS detector was used.Column: Waters XBridge ShieldRP18, 2.1×50 mm, 5 μm; Column temperature:40° C.; Solvent system: A=water/ammonia (99.95:0.05) and B=acetonitrile;Method: Linear gradient elution with A:B=95:5 to 0:100 in 4.0 minutesand with a flow rate of 0.8 mL/min.

Method C: An Agilent 1200 LCMS system with ELS detector was used.Phenomenex Luna-C18, 5 μm; 2.0×50 mm; Column temperature: 50° C.;Solvent system: A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile /trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=99:1 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method D: A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEHC18 1.7 μm; 2.1×50 mm; Column temperature: 60° C.; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/water/trifluoroacetic acid (94.965:5:0.035); Method:Linear gradient elution with A:B=90:10 to 0:100 in 1.0 minutes and witha flow rate of 1.2 mL/min.

Method E: A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEHC18 1.7 μm; 2.1×50 mm; Column temperature: 60° C.; Solvent system:A=water/formic acid (99.9:0.1) and B=acetonitrile/water/formic acid(94.9:5:0.1); Method: Linear gradient elution with A:B=90:10 to 0:100 in1.0 minutes and with a flow rate of 1.2 mL/min.

Method F: An Agilent 1200 LCMS system with ELS detector was used.Column: Waters XBridge ShieldRP18, 2.1×50 mm, 5 μm; Column temperature:40° C.; Solvent system: A=water/ammonia (99.95:0.05) and B=acetonitrile;Method: Linear gradient elution with A:B=85:15 to 0:100 in 3.4 minutesand with a flow rate of 0.8 mL/min.

Method G: An Agilent 1200 LCMS system with ELS detector was used.Column: Agilent TC-C18 5μm; 2.1×50 mm; Column temperature: 50° C.;Solvent system: A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=99:1 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method H: An Agilent 1200 LCMS system with ELS detector was used.Column: Waters XBridge ShieldRP18, 2.1×50 mm, 5 μm; Column temperature:40° C.; Solvent system: A=water/ammonia (99.95:0.05) and B=acetonitrile;Method: Linear gradient elution with A:B=70:30 to 0:100 in 3.4 minutesand with a flow rate of 0.8 mL/min.

Method I: An Agilent 1200 LCMS system with ELS detector was used.Phenomenex Luna-C18, 5 μm; 2.0×50 mm; Column temperature: 50° C.;Solvent system: A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=75:25 to 0:100 in 3.4 minutes and with a flowrate of 0.8 mL/min.

Method J: A Waters Autopurification was used. Column: XSelect CSH C183.5 micron, 4.6×50 mm; Column temperature: 25° C.; Solvent system:A=water/formic acid (99.9:0.1) and B=acetonitrile/trifluoroacetic acid(99.9:0.1); Method: Linear gradient elution with A:B=97:3 to 10:90 in2.5 minutes and with a flow rate of 2.5 mL/min.

Method K: A Waters Autopurification was used. Column: XSelect CSH C183.5 micron, 4.6×50 mm; Column temperature: 25° C.; Solvent system:A=water/formic acid (99.9:0.1) and B=acetonitrile/trifluoroacetic acid(99.9:0.1); Method: Linear gradient elution with A:B=97:3 to 10:90 in2.5 minutes, then with A:B=10:90 for 1 minute. The flow rate was 2.5mL/min.

Method L: An Agilent 1200 LCMS system with ELS detector was used. WatersXbridge-C18, 50×2 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.96:0.04) andB=acetonitrile/trifluoroacetic acid (99.98:0.02); Method: Lineargradient elution with A:B=90:10 to 0:100 in 3.4 minutes and with a flowrate of 0.8 mL/min.

Method M: An Agilent 1200 LCMS system with ELS detector was used. WatersXbridge-C18, 50×2 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.96:0.04) andB=acetonitrile/trifluoroacetic acid (99.98:0.02); Method: Lineargradient elution with A:B=99:1 to 0:100 in 3.4 minutes and with a flowrate of 0.8 mL/min.

INTERMEDIATES (for Compounds of the Invention and Supporting Examples)Preparation of ethyl 3-methyl-1H-pyrazole-5-carboxylate

A solution of ethyl 2,4-dioxopentanoate (20 g, 126 mmol, 18 mL) andhydrazine hydrate (6.96 g, 139 mmol, 6.76 mL) in ethanol (400 mL) wasstirred at 0° C. for 1 hour. The mixture was concentrated to give ethyl3-methyl-1H-pyrazole-5-carboxylate (19 g, 123 mmol, 97% yield).

Preparation of ethyl 1,3-dimethyl-1H-pyrazole-5-carboxylate

To a solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate (19.5 g, 126mmol) in DMF (200 mL) was added Me₂SO₄ (23.8 g, 189 mmol, 17.9 mL). Themixture was stirred at 80° C. for 18 hours. After cooling to 0° C., themixture was diluted with ice, then aqueous ammonia (25%) was added toadjust the pH to 8. Then the mixture was extracted with ethyl acetate(300 mL×3), the combined organic layers were washed with brine (50 mL),dried, and concentrated.

The crude mixture was purified by flash chromatography with petroleumether:ethyl acetate=5:1 to give ethyl1,3-dimethyl-1H-pyrazole-5-carboxylate (15 g, 89 mmol, 71% yield).

Preparation of ethyl 2-(methoxyimino)-4-oxopentanoate

A mixture of ethyl 2,4-dioxopentanoate (27 g, 171 mmol, 24 mL) andmethoxylamine (15 g, 179 mmol, 13.6 mL) in ethanol (150 mL) was stirredat 25° C. for 18 hours under a nitrogen atmosphere. The mixture wasconcentrated. The crude mixture was purified by flash silica gelchromatography with petroleum ether:ethyl acetate=10:1 to give ethyl2-(methoxyimino)-4-oxopentanoate (19.9 g, 103 mmol, 60% yield). ¹H NMR(chloroform-d 400 MHz): δ 4.34 (q, J=6.8 Hz, 2H), 4.07 (s, 3H), 3.71 (s,2H), 2.21 (s, 3H), 1.35 (d, J=7.6 Hz, 3H).

Preparation of ethyl 1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate

To a solution of ethyl 2-(methoxyimino)-4-oxopentanoate (14.6 g, 78.0mmol) in ethanol (200 mL) was added isopropylhydrazine hydrochloride(17.25 g, 156 mmol). The mixture was stirred at 80° C. for 18 hours. Themixture was concentrated. Saturated aqueous NaHCO₃ was added into theresidue to adjust the pH to 7. Then the mixture was extracted withdichloromethane (100 mL×3), the combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated. The crude mixture waspurified by flash silica gel chromatography with petroleum ether:ethylacetate=10:1 to give ethyl1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate (12.3 g, 62.7 mmol, 80%yield). ¹H NMR (chloroform-d 400 MHz): δ6.59 (s, 1H), 5.41-5.44 (m, 1H),4.35-4.29 (m, 2H), 2.29 (s, 3H), 1.48 (d, J=6.8 Hz, 6H), 1.39-1.35 (m,3H).

Preparation of ethyl1-isopropyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylate

To a solution of ethyl 1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate (8g, 40.8 mmol) and (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (59.9g, 285.4 mmol, 39.7 mL) in TFA (80 mL) was added ammonium nitrate (6.5g, 81.5 mmol, 3.8 mL) slowly at 0° C. The mixture was stirred at 20° C.for 18 hours. The solution was cooled to 0° C. and then neutralized withaqueous K₂CO₃ and the product was extracted with ethylacetate:dichloromethane=40:1 (205 mL×4). The combined organic layerswere washed with brine (150 mL), dried over Na₂SO₄ and concentrated togive ethyl 1-isopropyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylate (9.8g).

Ethyl 1-ethyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylate was prepared ina similar way from ethylhydrazine.

Ethyl 1-cyclopropyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylate wasprepared in a similar way from cyclopropylhydrazine.

(±)-Ethyl 1-(sec-butyl)-3-methyl-1H-pyrazole-5-carboxylate was preparedin a similar way from (±)-sec-butylhydrazine hydrochloride.

Preparation of ethyl 3-methyl-4-nitro-1H-pyrazole-5-carboxylate

Ethyl 3-methyl-1H-pyrazole-5-carboxylate (12 g, 78 mmol) was added inportions to fuming nitric acid (140 g, 2.2 mol, 100 mL) at 0° C. Themixture was stirred at 15° C. for 16 hours. The mixture was poured intoice (200 g) and adjusted to pH 7 by saturated aqueous K₂CO₃. The mixturewas extracted with ethyl acetate (500 mL×2). The organic layer waswashed with H₂O (500 mL), brine (500 mL), dried over Na₂SO₄, filteredand concentrated to give ethyl3-methyl-4-nitro-1H-pyrazole-5-carboxylate (13 g, 65 mmol, 84% yield).¹H NMR (chloroform-d 400 MHz) δ 11.41 (brs, 1H), 4.47-4.42 (m, 2H), 2.64(s, 3H), 1.39 (t, J=7.2 Hz, 3H).

Preparation of ethyl1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazole-5-carboxylate and ethyl1-(4-methoxybenzyl)-5-methyl-4-nitro-1H-pyrazole-3-carboxylate

To a solution of ethyl 3-methyl-4-nitro-1H-pyrazole-5-carboxylate (4.40g, 22.1 mmol) in dry DMF (50 mL) was added1-(chloromethyl)-4-methoxybenzene (4.15 g, 26.5 mmol, 3.6 mL) and K₂CO₃(6.11 g, 44.2 mmol). The mixture was stirred at 15° C. for 16 hours. Themixture was concentrated and water (20 mL) was added. The mixture wasextracted with ethyl acetate (20 mL×2). The combined organic layers werewashed with H₂O (20 mL×2), brine (20 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by flash chromatography onsilica gel (0% to 50% ethyl acetate in petroleum ether) to give ethyl1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazole-5-carboxylate (2.80 g,8.77 mmol, 40% yield) and ethyl1-(4-methoxybenzyl)-5-methyl-4-nitro-1H-pyrazole-3-carboxylate (3.50 g,11 mmol, 50% yield).

Preparation of ethyl4-amino-1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate

To a solution of ethyl1-isopropyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylate (10.23 g, 42.41mmol) in ethyl acetate (200 mL) was added Pd-C (10%, 2.0 g, wet) undernitrogen. The suspension was degassed under vacuo and purged withhydrogen several times. The mixture was stirred under hydrogen (30 psi)at 40° C. for 18 hours. The mixture was filtered and the residue waswashed with ethyl acetate (150 ml×3), the combined filtrates wereconcentrated to give ethyl4-amino-1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate (8.96 g).

Ethyl 4-amino-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-5-carboxylate wasprepared in a similar way from ethyl1-(4-methoxybenzyl)-3-methyl-4-nitro-1H-pyrazole-5-carboxylate.

Ethyl 4-amino-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate was prepared ina similar way from ethyl1-ethyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylate.

Ethyl 4-amino-1-cyclopropyl-3-methyl-1H-pyrazole-5-carboxylate wasprepared in a similar way from ethyl1-cyclopropyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylate.

Ethyl 4-amino-1,3-dimethyl-1H-pyrazole-5-carboxylate was prepared in asimilar way from ethyl 1,3-dimethyl-4-nitro-1H-pyrazole-5-carboxylate.

(±)-Ethyl 4-amino-1-(sec-butyl)-3-methyl-1H-pyrazole-5-carboxylate wasprepared in a similar way from (±)-ethyl1-(sec-butyl)-3-methyl-1H-pyrazole-5-carboxylate.

Preparation of ethyl1-isopropyl-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylate

To a solution of ethyl4-amino-1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate (7.96 g, 37.7mmol) in dichloromethane (150 mL) was added methyl3-chloro-3-oxopropanoate (5.14 g, 37.7 mmol, 4.02 mL). The mixture wasstirred at 50° C. for 45 minutes. After the reaction mixture had cooledto room temperature, the mixture was partitioned between dichloromethane(200 mL) and saturated aqueous NaHCO₃ (100 mL), the aqueous phase wasextracted with dichloromethane (100 mL×2), the combined organic layerswere washed with brine (50 mL), dried over MgSO₄ and concentrated togive ethyl1-isopropyl-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylate(11.7 g, 37 mmol, >95% yield).

Ethyl4-(3-methoxy-3-oxopropanamido)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-5-carboxylatewas prepared in a similar way from ethyl4-amino-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-5-carboxylate.

Ethyl1-ethyl-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylatewas prepared in a similar way fromethyl4-amino-1-ethyl-3-methyl-1H-pyrazole-5-carboxylate.

Ethyl1-cyclopropyl-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylatewas prepared in a similar way from ethyl4-amino-1-cyclopropyl-3-methyl-1H-pyrazole-5-carboxylate.

Ethyl4-(3-methoxy-3-oxopropanamido)-1,3-dimethyl-1H-pyrazole-5-carboxylatewas prepared in a similar way from ethyl4-amino-1,3-dimethyl-1H-pyrazole-5-carboxylate.

(±)-Ethyl1-(sec-butyl)-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylatewas prepared in a similar way from (±)-ethyl4-amino-1-(sec-butyl)-3-methyl-1H-pyrazole-5-carboxylate.

Preparation of methyl5,7-dihydroxy-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate

To a solution of ethyl1-isopropyl-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylate(12.5 g, 40 mmol) in ethanol (200 mL) was added NaOEt (5.45 g, 80 mmol).The mixture was stirred at 20° C. for 1 hour. The mixture wasconcentrated. The crude product (10.62 g) was used into the next stepwithout further purification.

Methyl5,7-dihydroxy-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylatewas prepared in a similar way from ethyl4-(3-methoxy-3-oxopropanamido)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-5-carboxylate.

Methyl1-ethyl-5,7-dihydroxy-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylatewas prepared in a similar way from ethyl1-ethyl-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylate.

Methyl1-cyclopropyl-5,7-dihydroxy-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylatewas prepared in a similar way from ethyl1-cyclopropyl-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylate.

Methyl5,7-dihydroxy-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate wasprepared in a similar way from ethyl4-(3-methoxy-3-oxopropanamido)-1,3-dimethyl-1H-pyrazole-5-carboxylate.

(±)-Methyl1-(sec-butyl)-5,7-dihydroxy-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylatewas prepared in a similar way from (±)-ethyl1-(sec-butyl)-4-(3-methoxy-3-oxopropanamido)-3-methyl-1H-pyrazole-5-carboxylate.

Preparation of 1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol

A mixture of methyl5,7-dihydroxy-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate(10.62 g, 40.04 mmol) in aqueous NaOH (2 N, 150 mL) was stirred at 110°C. for 6 hours. The mixture was cooled to 0° C., then saturated aqueousKHSO₄ was added to adjust the pH to 2˜3. The resulting mixture wasfiltered and the residue was washed with water (50 mL×3), then dried togive 1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol (7 g,32.43 mmol, 81% yield). ¹H NMR (DMSO-d₆ 400 MHz) δ 11.02 (brs, 1H), 5.50(s, 1H), 5.11-5.08 (m, 1H), 2.24 (s, 3H), 1.37 (d, J=6.8 Hz, 6H).

1-(4-Methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol wasprepared in a similar way from methyl5,7-dihydroxy-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate.

1-ethyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol was prepared in asimilar way from methyl1-ethyl-5,7-dihydroxy-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate.

1-cyclopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol was preparedin a similar way from methyl1-cyclopropyl-5,7-dihydroxy-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate.

1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol was prepared in asimilar way from1-cyclopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol.

(±)-1-(sec-Butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol wasprepared in a similar way from (±)-methyl1-(sec-butyl)-5,7-dihydroxy-3-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylate.

Preparation of5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine

A mixture of 1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol(3.50 g, 16.9 mmol) in phosphoryl trichloride (30 mL) was stirred at 80°C. for 18 hours. The mixture was stirred at 85° C. for another 1 hour.The mixture was concentrated and then water (50 mL) was added slowly,followed by saturated aqueous NaHCO₃ to adjust pH to 7. The aqueousphase was extracted with ethyl acetate (70 mL×3), the combined organiclayers were washed with brine (50 mL), dried over Na₂SO₄ andconcentrated. The crude product was purified by flash chromatographywith petroleum ether:ethyl acetate=20:1 to give5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine (3.50 g,14.3 mmol, 85% yield). ¹H NMR (chloroform-d 400 MHz) δ 7.28 (s, 1H),5.48-5.41 (m, 1H), 2.62 (s, 3H), 1.57 (d, J=4.8 Hz, 6H).

The following compounds were prepared in a similar manner:

5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine from1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol and phosphoryltribromide. ¹H NMR (chloroform-d 400 MHz) δ 7.60 (s, 1H), 5.61-5.55 (m,1H), 2.63 (s, 3H), 1.57 (d, J=6.4 Hz, 6H).

5,7-dibromo-1-ethyl-3-methyl-1H-pyrazolo[4,3-b]pyridine from1-ethyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol and phosphoryltribromide.

5,7-dichloro-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine from1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol and phosphoryltrichloride.'HNMR (chloroform-d 400 MHz) δ 7.29 (s, 1H), 4.29 (s, 3H),2.60 (s, 3H).

(±)-5,7-Dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine from(±)-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol andphosphoryl tribromide.

5,7-dibromo-1-cyclopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine from1-cyclopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol andphosphoryl tribromide. ¹H NMR (chloroform-d 400 MHz) δ 7.63 (s, 1H),3.99-3.88 (m, 1H), 2.57 (s, 3H), 1.41-1.38 (m, 2H), 1.22-1.19 (m, 2H).

5,7-Dibromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine from1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-5,7-diol andphosphoryl tribromide.

Preparation of 5,7-dibromo-3-methyl-1H-pyrazolo[4,3-b]pyridine

A solution of5,7-dibromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine (650mg, 1.58 mmol) in TFA (5 mL) was heated at 80° C. for 2 hours. Themixture was concentrated and the residue was dissolved in H₂O (5 mL).The mixture was adjusted to pH 7 by saturated aqueous. NaHCO₃ andextracted with ethyl acetate (20 mL×2). The combined organic layers werewashed with H₂O (20 mL), brine (20 mL), dried over Na₂SO₄, filtered andconcentrated to give 5,7-dibromo-3-methyl-1H-pyrazolo[4,3-b]pyridine(450 mg, 1.55 mmol, 98% yield).

Preparation of5,7-dibromo-3-methyl-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridine

To a solution of 5,7-dibromo-3-methyl-1H-pyrazolo[4,3-b]pyridine (340mg, 1.17 mmol) in dry DMF (10 mL) was added 3-iodooxetane (323 mg, 1.76mmol) and Cs₂CO₃ (762 mg, 2.34 mmol). The mixture was heated undermicrowave at 100° C. for 1 hour. The mixture was concentrated and water(20 mL) was added. The mixture was extracted with ethyl acetate (20mL×2). The combined organic layers were washed with H₂O (20 mL×2), brine(20 mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on silica gel (0% to 50% ethyl acetatein petroleum ether) to give5,7-dibromo-3-methyl-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridine (200 mg,49% yield).

Preparation of(+5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine and(+)-5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine

(±)-5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine (2.2g, 6.34 mmol) was purified by SFC twice to give(+)-5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine (800mg) (Rt=6.25 min) and(+5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine (900 mg)(Rt=6.28 min).

(+)-5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine ¹H NMR(Chloroform-d, 400 MHz): δ 7.60 (s, 1H), 5.41-5.32 (m, 1H), 2.63 (s,3H), 2.13-2.07 (m, 1H), 1.87-1.83 (m, 1H), 1.54 (d, J=6.4 Hz, 3H), 0.79(t, J=7.6 Hz, 3H). SFC-MS: t_(R)=6.25 min, ee %=100%; [α]_(D) ²⁰=2.60(c=1.0, dichloromethane).

(−)-5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridinel-HNMR(Chloroform-d, 400 MHz): δ 7.60 (s, 1H), 5.41-5.32 (m, 1H), 2.63 (s,3H), 2.13-2.07 (m, 1H), 1.87-1.83 (m, 1H), 1.55 (d, J=6.8 Hz, 3H), 0.79(t, J=7.6 Hz, 3H). SFC-MS: t_(R)=6.5 min, ee %=97.87%; [α]_(D) ²⁰=−2.90(c=1.0, dichloromethane).

SFC Condition 1:

Instrument: Thar SFC 1; Column:(s,$) WHELK-01 (250 mm×30 mm,5 μm);Mobile phase: A: Supercritical CO₂, B: isopropyl alcohol (0.1% NH₃H₂O),A: B=85:15 at 60 ml/min; Column Temp: 38° C.; Nozzle Pressure: 100 Bar;Nozzle Temp: 60° C.; Evaporator Temp: 20° C.; Trimmer Temp: 25° C.;Wavelength: 220 nm

SFC Condition 2:

Instrument: Thar SFC-13; Column:(s,s) WHELK-01 (250 mm×30 mm, 5 μm);Mobile phase: A: Supercritical CO₂, B: isopropyl alcohol (0.1% NH₃H₂O),A: B=85:15 at 60 ml/min; Column Temp: 38° C.; Nozzle Pressure: 100 Bar;Nozzle Temp: 60° C.; Evaporator Temp: 20° C.; Trimmer Temp: 25° C.;Wavelength: 220 nm

Preparation of 4,6-dibromo-2-methylpyridin-3-amine

A solution of 6-bromo-2-methylpyridin-3-amine (24 g, 128 mmol) and AcOH(14.7 mL 257 mmol) in MeOH (200 mL) was cooled to 0° C., Br₂ (36.9 g,230.9 mmol, 11.9 mL) was added and stirred at 0° C. for 5 hours. Themixture was quenched with saturated aqueous Na₂SO₃ (500 mL), extractedwith ethyl acetate (300 mL×3). The organic layer was washed with brine(200 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue waspurified by silica gel chromatography (petroleum ether:ethylacetate=2:1) to afford 4,6-dibromo-2-methylpyridin-3-amine (30 g, 87%yield).

Preparation of 5,7-dibromo-1H-pyrazolo[4,3-b]pyridine

To a mixture of 4,6-dibromo-2-methylpyridin-3-amine (15.0 g, 56.4 mmol)and AcOK (13.8 g, 141 mmol) in AcOH (30 mL) and toluene (200 mL) wasadded isopentyl nitrite (13.2 g, 112.8 mmol). The mixture was stirred at25° C. for 1 hour then at 60° C. for 19 hours. The mixture wasconcentrated in vacuo, diluted with water (300 mL) and extracted withethyl acetate (200 mL×2). The organic layer was washed with brine (100mL), dried over Na₂SO₄ and concentrated in vacuo to give5,7-dibromo-1H-pyrazolo[4,3-b]pyridine (5.4 g, 30% yield).

Preparation of 5,7-dibromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine

To a mixture of 5,7-dibromo-1H-pyrazolo[4,3-b]pyridine (1 g, 3.6 mmol)and Cs₂CO₃ (12.4 g, 7.2 mmol) in anhydrous DMF (10 mL) was addediodoethane (0.8 g, 5.4 mmol). The mixture was stirred at 0° C. for 0.5hours. The mixture was diluted with water (20 mL), extracted with ethylacetate (30 mL×2). The organic layer was washed with water (20 mL),brine (20 mL) and dried with Na₂SO₄, concentrated in vacuo. The residuewas purified by silica gel chromatography (petroleum ether:ethylacetate=10:1-5:1) to give 5,7-dibromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine(0.56 g, 51% yield). ¹H NMR (DMSO-d₆ 400 MHz) δ 8.37 (s, 1H), 7.98 (s,1H), 4.72 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).

The following compounds were prepared in a similar manner:

5,7-Dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine from5,7-dibromo-1H-pyrazolo[4,3-b]pyridine and 2-iodopropane. ¹H NMR(DMSO-d₆ 400 MHz) δ 8.36 (s, 1H), 7.94 (s, 1H), 5.62-5.55 (m, 1H), 1.49(d, J=6.0 Hz, 6H).

5,7-Dibromo-1-propyl-1H-pyrazolo[4,3-b]pyridine from5,7-dibromo-1H-pyrazolo[4,3-b]pyridine and 1-iodopropane. ¹H NMR(chloroform-d 400 MHz) δ 8.14 (s, 1H), 7.64 (s, 1H), 4.67 (t, J=7.2 Hz,2H), 1.98-1.89 (m, 2H), 0.94 (t, J=7.6 Hz, 3H).

5,7-Dibromo-1-methyl-1H-pyrazolo[4,3-b]pyridine from5,7-dibromo-1H-pyrazolo[4,3-b]pyridine and iodomethane. ¹H NMR(chloroform-d 400 MHz) δ 8.13 (s, 1H), 7.64 (s, 1H), 4.38 (s, 3H).

(±)-5,7-Dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine from5,7-dibromo-1H-pyrazolo[4,3-b]pyridine and (±)-2-iodobutane.

Preparation of (+)-5,7-dibromo-1-(sec-butyl)-1H-pyrazolo[4,3-b]pyridineand (−)-5,7-dibromo-1-(sec-butyl)-1H-pyrazolo[4,3-b]pyridine

(±)-5,7-dibromo-1-sec-butyl-pyrazolo[4,3-b]pyridine (5.2 g, 15.6 mmol)was separated by SFC with column: AD(250 mm*50 mm,10 μm);mobile phase:[0.1% NH₃H₂O in isopropyl alcohol]; B %: 20%-20%, min.

(+)-5,7-dibromo-1-(sec-butyl)-1H-pyrazolo [4,3-b]pyridine (2.5 g)(Rt=3.137 min) ([α]_(D) ²⁰=1.40) (c=1.0, ethanol).

(−)-5,7-dibromo-1-(sec-butyl)-1H-pyrazolo[4,3-b]pyridine (2.5 g)(Rt=2.808 min) ([a]_(D) ²⁰=−1.60) (c=1.0, ethanol).

Preparation of5-chloro-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

To a solution of5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine (100 mg,410 μmol) and (4-methoxyphenyl)methanamine (67 mg, 492 μmol, 64 μL) inNMP (5 mL) was added CsF (124 mg, 819 umol, 30 μL). The mixture wasstirred at 100° C. for 18 hours. Water (20 mL) was added and the mixturewas filtered and concentrated in vacuo. The crude mixture was purifiedby flash chromatography with petroleum ether:ethyl acetate=3:1 to give5-chloro-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(80 mg, 215 μmol, 53% yield). ¹H NMR (chloroform-d 400 MHz) δ 7.32 (d,J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.39 (s, 1H), 4.79 (brs, 1H),4.70-4.63 (m, 1H), 4.39 (d, J=4.4 Hz, 2H), 3.85 (s, 3H), 2.56 (s, 3H),1.57 (d, J=6.4 Hz, 6H).

Preparation of5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

To a solution of5-chloro-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(60 mg, 174 μmol) in dioxane (2 mL) and H₂O (0.5 mL) was addedPd(1,1′-bis(diphenylphosphino)ferrocene)Cl₂ (25 mg, 35 μmol) and Cs₂CO₃(141.72 mg, 435 μmol) and (2-ethoxypyridin-3-yl)boronic acid (52 mg, 313umol). The mixture was stirred at 100° C. for 1 hour under microwaveirradiation. Water (30 mL) was added and the mixture was extracted withethyl acetate (30 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄ and concentrated. The crude mixture waspurified by flash chromatography with petroleum ether:ethyl acetate=1:1to 0:1 to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(50 mg, 67% yield). ¹H NMR (chloroform-d 400 MHz) δ 8.27-8.25 (m, 1H),8.17-8.16 (m, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.22 (s, 1H), 7.03-7.00 (m,1H), 6.95 (d, J=8.4 Hz, 2H), 4.81-4.76 (m, 1H), 4.65 (brs, 1H),4.47-4.41 (m, 4H), 3.84 (s, 3H), 2.65 (s, 3H), 1.60 (d, J=6.4 Hz, 6H),1.36 (t, J=7.2 Hz, 3H).

The following compounds were prepared in a similar manner:

5-(2-Fluoropyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from5-bromo-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand (2-fluoropyridin-3-yl)boronic acid.

3-(1-Isopropyl-7-((4-methoxybenzyl)amino)-3-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2(1H)-one

Prepared from5-chloro-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand (2-oxo-1,2-dihydropyridin-3-yl)boronic acid.

Preparation of5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

A solution of5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(1.25 g, 2.90 mmol) in TFA (15 mL) was stirred at 60° C. for 18 hours.The mixture was concentrated and the residue was dissolved in ethylacetate (200 mL). The resulting mixture was washed with saturatedaqueous NaHCO₃ (30 mL), brine (20 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by flash chromatographywith petroleum ether:ethyl acetate=3:1 to 2:1 to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(900 mg, 96% yield).

The following compounds were prepared in a similar manner:

5-(2-Ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amine

5-(2-Ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

1-Isopropyl-3-methyl-5-(2-propoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

1-(sec-Butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1, prepared from(+)-5,7-dibromo-1-(sec-butyl)-1H-pyrazolo[4,3-b]pyridine

1-(sec-Butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2, prepared from(−)-5,7-dibromo-1-(sec-butyl)-1H-pyrazolo[4,3-b]pyridine

1-(sec-Butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1, prepared from(+)-5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine

1-(sec-Butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2, prepared from(−)-5,7-dibromo-1-(sec-butyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine1-Isopropyl-5-(2-methoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from1-isopropyl-N-(4-methoxybenzyl)-5-(2-methoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine5-(2-(Dimethylamino)pyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from5-(2-(dimethylamino)pyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine3-(7-Amino-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-5-yOpyridin-2(1H)-one

Prepared from3-(1-isopropyl-7-((4-methoxybenzyl)amino)-3-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2(1H)-onePreparation of ethyl 3-methyl-1,2,4-oxadiazole-5-carboxylate

To a solution of ethyl 2-chloro-2-oxoacetate (1 g, 13.5 mmol) andpyridine (4.27 g, 54 mmol, 4.36 mL) in dichloromethane (40 mL) was addedat 15-20° C. N′-hydroxyacetimidamide (2.40 g, 17.5 mmol, 1.96 mL). Thesolution was stirred at 50° C. for 14 hours. The reaction mixture wascooled and quenched with saturated aqueous NH₄Cl (30 mL). The aqueousphase was extracted with dichloromethane (2×50 mL). The organic phaseswere combined, washed with saturated aqueous NaHCO₃ (50 mL), dried overMgSO₄, filtered and concentrated under reduced pressure to give ethyl3-methyl-1,2,4-oxadiazole-5-carboxylate (2.80 g, 44% yield).

Preparation of (3-methyl-1,2,4-oxadiazol-5-yl)methanol

To a solution of ethyl 3-methyl-1,2,4-oxadiazole-5-carboxylate (2.10 g,13.5 mmol) in THF (10 mL) and ethanol (10 mL) was added NaBH₄ (1.02 g,26.9 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. Themixture was quenched with saturated aqueous NH₄Cl, and concentrated invacuo. The residue was dissolved in dichloromethane (50 mL) andfiltered; the filtrate was dried over Na₂SO₄ and concentrated in vacuoto give (3-methyl-1,2,4-oxadiazol-5-yl)methanol (800 mg, 52% yield).

Preparation of 3-methyl-1,2,4-oxadiazole-5-carbaldehyde

A solution of oxalyl chloride (267 mg, 2.10 mmol, 184 μL) in drydichloromethane (5 mL) was cooled to −78° C. and then DMSO (219 mg, 2.80mmol) was added. The mixture was stirred at −78° C. for 15 minutes. Asolution of (3-methyl-1,2,4-oxadiazol-5-yl)methanol (80 mg, 0.70 mmol)in dichloromethane (0.5 mL) was added at −78° C. The mixture was stirredat −78° C. for 1 hour. Then triethylamine (0.58 mL, 4.2 mmol) was addedat −78° C. The mixture was warmed to 20° C. and stirred at 20° C. for 1hour. The mixture was poured into 1 N aqueous HCl (5 mL). The mixturewas extracted with dichloromethane (20 mL×2). The combined organiclayers were washed with H₂O (20 mL), dried over Na₂SO₄, filtered andconcentrated to give 3-methyl-1,2,4-oxadiazole-5-carbaldehyde (80 mg).¹H NMR (chloroform-d 400 MHz) δ 9.97 (s, 1H), 2.55 (s, 3H).

Preparation of 1-methyl-1H-1,2,4-triazole-3-carbaldehyde

To a mixture of (1-methyl-1H-1,2,4-triazol-3-yl)methanol (400 mg, 3.54mmol) and iodobenzene diacetate (1.25 g, 3.89 mmol) in dichloromethane(10 mL) was added TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) (56mg, 354 μmol). The mixture was stirred at 15-20° C. for 2 h. The mixturewas concentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=1:2) to give1-methyl-1H-1,2,4-triazole-3-carbaldehyde (300 mg, 2.70 mmol, 76%yield). ¹H NMR (chloroform-d 400 MHz) δ 10.01 (s, 1H), 8.19 (s, 1H),4.06 (s, 3H).

Preparation of ethyl 2-(2-acetylhydrazinyl)-2-oxoacetate

To a solution of acetohydrazide (5 g, 67 mmol) in dichloromethane (150mL) was added N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (16.7 g, 67mmol). The mixture was stirred at 15° C. for 10 minutes. Then ethyl2-chloro-2-oxoacetate (9.22 g, 67.5 mmol, 7.56 mL) was dropwise added tothe mixture. The mixture was stirred at 15° C. for 16 hours. The mixturewas washed with H₂O (100 mL) and extracted with dichloromethane (100mL×3). The combined organic phases were dried over Na₂SO₄ andconcentrated under vacuo. The residue was purified with columnchromatography (SiO₂, petroleum ether:ethyl acetate=1:0 to 0:1) to giveethyl 2-(2-acetylhydrazinyl)-2-oxoacetate (9.30 g, 79% yield).

Preparation of ethyl 5-methyl-1,3,4-thiadiazole-2-carboxylate

To a solution of ethyl 2-(2-acetylhydrazinyl)-2-oxoacetate (3 g, 17mmol) in THF (100 mL) was added Lawesson's reagent (7.66 g, 19 mmol).The mixture was stirred at 75° C. for 3 hours. The mixture was dilutedwith ethyl acetate (500 mL) and added approximately 40 g ofdecolourising charcoal. The mixture was stirred at 18° C. for 16 hours.The mixture was filtered. The filtrate was concentrated under vacuo. Theresidue was purified with column chromatography (SiO₂, petroleumether:ethyl acetate=3:7) to give ethyl5-methyl-1,3,4-thiadiazole-2-carboxylate (921 mg, 28% yield).

Preparation of 5-methyl-1,3,4-thiadiazole-2-carbaldehyde

To a solution of ethyl 5-methyl-1,3,4-thiadiazole-2-carboxylate (400 mg,2.32 mmol) in dry THF (5 mL) was dropwise added DIBAL-H(diisobutylaluminium hydride) (1 M in toluene, 6.97 mL). The mixture wasstirred at −40° C. for 2 hours. The mixture was quenched with saturatedaqueous NH₄Cl (5 mL) and filtered. The solution was extracted withdichloromethane (15 mL×3). The combined organic phases were dried overNa₂SO₄ and concentrated under vacuo. The residue was purified withpreparative TLC (petroleum ether:ethyl acetate=1:1) to give5-methyl-1,3,4-thiadiazole-2-carbaldehyde (123 mg, 41% yield). ¹H NMR(chloroform-d 400 MHz) δ 10.19 (s, 1H), 2.92 (s, 3H).

Preparation of (5-methylthiophen-3-yl)methanol

To a solution of 5-methylthiophene-3-carboxylic acid (300 mg, 2.11 mmol)in THF (10 mL) was added LiAlH₄ (120 mg, 3.17 mmol) slowly at 0° C. Themixture was stirred at 20° C. for 2 hours. Water (0.3 mL) was added at0° C. to quench the reaction mixture followed by addition of 15% aqueousNaOH (0.3 mL). Ethyl acetate (50 mL) was added to the mixture, themixture was filtered and the residue was washed with ethyl acetate (20mL×2). The combined filtrates were dried over Na₂SO₄ and concentrated togive (5-methylthiophen-3-yl)methanol (270 mg).

Preparation of (5-methyloxazol-2-yl)methanol

To the reaction mixture of ethyl 5-methyloxazole-2-carboxylate (500 mg,3.22 mmol) in ethanol (10 mL) was added NaBH₄ (609 mg, 16.10 mmol) withstirring at 20° C. Then resulting solution was stirred at 20° C. for 3hours. The reaction was quenched by water (50 mL), then concentratedunder reduced pressure to remove the ethanol. The residue was extractedby ethyl acetate (50 mL×3). The combined organic layers were washed withbrine (10 mL), dried over Na₂SO₄, concentrated to give(5-methyloxazol-2-yl)methanol (364 mg).

Preparation of 5-methylthiophene-3-carbaldehyde

To a solution of (5-methylthiophen-3-yl)methanol (270 mg, 2.11 mmol) indichloromethane (10 mL) was added Dess-Martin reagent(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one) (1.07 g, 2.53mmol).The mixture was stirred at 20° C. for 1 hour. The mixture wasfiltered and the residue was washed with dichloromethane (30 mL), thecombined organic layers were concentrated. The crude mixture waspurified by flash chromatography with petroleum ether: ethyl acetate=5:1to give 5-methylthiophene-3-carbaldehyde (180 mg, 1.43 mmol, 68% yield).¹H NMR (chloroform-d 400 MHz) δ 9.81 (s, 1H), 7.89 (s, 1H), 7.20 (s,1H), 2.51 (s, 3H).

The folowing compounds were prepared in a similar manner:

5-methyloxazole-2-carbaldehyde from (5-methyloxazol-2-yl)methanol

3-methylisoxazole-5-carbaldehyde from (3-methylisoxazol-5-yl)methanol

5-methyl-1,2,4-oxadiazole-3-carbaldehyde from(5-methyl-1,2,4-oxadiazol-3-yl)methanol

1,5-dimethyl-1H-pyrazole-3-carbaldehyde from(1,5-dimethyl-1H-pyrazol-3-yl)methanol

Preparation of 1-((1-aminoethyl)thio)-3-chloropropan-2-one

A solution of ethanethioamide (1 g, 13.3 mmol) in acetone (7 mL) wasadded dropwise to a solution of 1,3-dichloropropan-2-one (1.69 g, 13.3mmol, 1.66 mL) in acetone (5 mL) at 20° C. and stirred at 20° C. for 12hours. The mixture was filtered and the filter cake was washed withacetone (10 mL×3) to give 1-((1-aminoethyl)thio)-3-chloropropan-2-one.

Preparation of 4-(chloromethyl)-2-methylthiazole

A mixture of 1-((1-aminoethyl)thio)-3-chloropropan-2-one (3 g, 17.9mmol) in ethanol (30 mL) was stirred at 80° C. for 2 h. The mixture wasconcentrated in vacuo to give 4-(chloromethyl)-2-methylthiazole (2.9 g).

Preparation of 2-((2-methylthiazol-4-yl)methyl)isoindoline-1,3-dione

To a mixture of 4-(chloromethyl)-2-methylthiazole (2.80 g, 19.0 mmol)and isoindoline-1,3-dione in anhydrous DMF (30 mL) was added K₂CO₃ (1.31g, 9.49 mmol). The mixture stirred at 100° C. for 0.5 hour. The mixturewas diluted with water (50 mL), extracted with ethyl acetate (50 mL×2).The organic layer was washed with water (30 mL), brine (30 mL), driedwith Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel chromatography (petroleum ether:ethyl acetate=10:1-2:1) togive 2-((2-methylthiazol-4-yl)methyl)isoindoline-1,3-dione (3.29 g).

Preparation of (2-methylthiazol-4-yl)methanamine

A mixture of 2-((2-methylthiazol-4-yl)methyl)isoindoline-1,3-dione (1 g,3.87 mmol) and hydrazine hydrate (291 mg, 5.81 mmol, 282 μL) in ethanol(10 mL) was stirred at 20° C. for 0.5 hour. The mixture was concentratedin vacuo. The residue was purified by silica gel chromatography(dichloromethane:methanol=0:1 to 10:1) to give(2-methylthiazol-4-yl)methanamine (330 mg).

Preparation of benzyl (cyanomethyl)carbamate

A mixture of 2-aminoacetonitrile hydrochloride (5 g, 54.0 mmol), NaHCO₃(18.16 g, 216 mmol) and dioxane (50 mL) in H₂O (100 mL) was stirred at0° C. Then a solution of benzyl carbonochloridate (11.06 g, 64.8 mmol,9.22 mL) in toluene (10 mL) was added at 0° C. and stirred at 20° C. for12 hours. The mixture was poured into water (100 mL), and the aqueousphase was extracted with ethyl acetate (100 mL×3). The combined organicphases were washed with brine (100 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel chromatography to give benzyl (cyanomethyl)carbamate (1.70 g). ¹HNMR (chloroform-d 400 MHz): 7.40-7.31 (m, 5H), 5.35-5.13 (m, 3H),4.16-4.12 (m, 2H).

Preparation of benzyl ((2H-tetrazol-5-yl)methyl)carbamate

A mixture of benzyl (cyanomethyl)carbamate (200 mg, 1.05 mmol), sodiumazide (250 mg, 3.85 mmol) zinc dibromide (118 mg, 525 umol) andisopropyl alcohol (2 mL) in H₂O (4 mL) was stirred at 100° C. for 24hours. The mixture was poured into water (50 mL), and added KHSO₄ (aq.)until pH=2. The aqueous phase was extracted with ethyl acetate (20mL×3). The combined organic phases were washed with brine (10 mL), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by silica gel chromatography (petroleum ether/ethylacetate=10/1 to 3/1) to give benzyl ((2H-tetrazol-5-yl)methyl)carbamate(200 mg).

Preparation of benzyl ((2-methyl-2H -tetrazol-5-yl)methyl)carbamate

To a mixture of benzyl ((2H-tetrazol-5-yl)methyl)carbamate (1 g, 4.29mmol) and K₂CO₃ (1.19 g, 8.58 mmol) in DMF (20 mL) was added CH₃I (0.91g, 6.4 mmol) at 0° C., and the reaction mixture was stirred at 30° C.for 12 hours. The mixture was filtrated and the filtrate wasconcentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=10/1 to 3/1) to givebenzyl ((2-methyl-2H-tetrazol-5-yl)methyl)carbamate (400 mg).

Preparation of (2-methyl-2H-tetrazol-5-yl)methanamine

To a solution of benzyl ((2-methyl-2H-tetrazol-5-yl)methyl)carbamate(250 mg, 1.0 mmol) in MeOH (10 mL) was added Pd/C(10%, wet) (10 mg)under N₂. The suspension was degassed in vacuo and purged with H2several times. The mixture was stirred under H₂ (15 psi) at 25° C. for12 hours. The mixture was filtered and the filtrate was concentratedunder vacuum to give (2-methyl-2H-tetrazol-5-yl)methanamine (120 mg,crude).

Preparation of m-tolylmethanamine hydrochloride

A mixture 3-methylbenzaldehyde (500 mg, 4.16 mmol, 490.20 μL) inNH₃/MeOH (7 M, 1 mL) was stirred at 80° C. for 14 hours. Then NaBH₄ (315mg, 8.32 mmol) was added and the reaction mixture was stirred at 20° C.for 1 hour. The mixture was diluted with water (20 mL) and extractedwith ethyl acetate (20 mL×2). The organic layers were washed with water(10 mL), brine (10 mL), dried with Na₂SO₄ and concentrated in vacuo. Theresidue was purified by preparative HPLC to give m-tolylmethanamine (370mg) as the HCl salt.

Preparation of p-tolylmethanol

To a suspension of LiAlH₄ (5.56 g, 147 mmol) in anhydrous THF (100 mL)was added a solution of methyl 4-methylbenzoate (11 g, 73.3 mmol) inanhydrous THF (50 mL), and the resulting mixture was stirred at 0° C.for 1 hour. The reaction mixture was quenched by addition H₂O (5 mL),15% aqueous NaOH(5 mL) and H₂O (8 mL) at 0° C., 8 g of anhydrous Na₂SO₄was added and the reaction mixture was filtered. The filtered cake waswashed with additional THF (80 mL×3). The combined organic layers wereconcentrated to give p-tolylmethanol (8.30 g, 93% yield). ¹H NMR(chloroform-d 400 MHz) δ 7.26 (d, J=8.0 Hz, 2H), 7.18 (d, J=7.6 Hz, 2H),4.65 (d, J=5.2 Hz, 2H), 2.36 (s, 3H).

Preparation of 1-(bromomethyl)-4-methylbenzene

To a solution of p-tolylmethanol (8.30 g, 68 mmol) in dichloromethane(200 mL) was added tribromophosphane (20.2 g, 74.7 mmol). The mixturewas stirred at 0° C. for 1 hour. The reaction mixture was poured intoH₂O (10 mL) and extracted with dichloromethane (25 mL), The organicphase was separated, washed with brine (10 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give1-(bromomethyl)-4-methylbenzene (12.5 g, 99% yield). ¹H NMR(chloroform-d 400 MHz) δ 7.29 (d, J=7.6 Hz, 2H), 7.16 (d, J=7.6 Hz, 2H),4.50 (s, 2H), 2.36 (s, 3H).

Preparation of 2-(4-methylbenzyl)isoindoline-1,3-dione

To a solution of 1-(bromomethyl)-4-methylbenzene (5 g, 27 mmol) in DMF(30 mL) was added potassium 1,3-dioxoisoindolin-2-ide (7.51 g, 40.5mmol). The mixture was stirred at 100° C. for 14 hours. The reactionmixture was concentrated under reduced pressure to remove DMF. Theresidue was purified by column chromatography (SiO₂, petroleumether:ethyl acetate=0 to 20%) to give2-(4-methylbenzyl)isoindoline-1,3-dione (5.50 g, 81% yield). ¹H NMR(chloroform-d 400 MHz) δ 7.85 (d, J=3.2 Hz, 2H), 7.84 (d, J=3.2 Hz, 2H),7.34 (d, J=7.6 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 4.82 (s, 2H), 2.32 (s,3H).

Preparation of p-tolylmethanamine

A mixture of 2-(4-methylbenzyl)isoindoline-1,3-dione (1 g, 3.8 mmol) andhydrazine hydrate (752 mg, 15 mmol, 730 μL) in MeOH (10 mL) was stirredat 20° C. for 3 hours. The mixture was concentrated in vacuo. Theresidue was purified by silica gel chromatography(dichloromethane:methanol (with 5% ammonia in water)=0:1 to 5:1) to givep-tolylmethanamine (160 mg).

Preparation of ethyl 5-methyl-1,2,4-oxadiazole-3-carboxylate

To a solution of hydroxylamine hydrochloride (1.71 g, 24.6 mmol) inacetic acid (10 mL) was added ethyl carbonocyanidate (2.00 g, 20.18mmol, 1.98 mL, 1.00 eq) and NaOAc (2.02 g, 24.62 mmol, 1.22 eq) at roomtemperature and the reaction mixture was for stirred 0.5 hours. To thereaction mixture was added acetic anhydride (3.25 mL, 34.7 mmol) at roomtemperature and the reaction mixture was stirred for 0.5 hours. Then itwas stirred at 100° C. for 12 hours. The mixture was cooled to roomtemperature, and acetic acid was removed under vacuo. Ethyl acetate (25mL) and water (5 mL) were added to the reaction mixture. The solutionwas neutralized with K₂CO₃ (aq.) to pH 7. The aqueous phase wasextracted with ethyl acetate (5 mL×3). The combined organic phases werewashed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by preparative HPLC togive ethyl 5-methyl-1,2,4-oxadiazole-3-carboxylate (1.40 g).

Preparation of (5-methyl-1,2,4-oxadiazol-3-yl)methanol

To a solution of 5-methyl-1,2,4-oxadiazole-3-carboxylate (400 mg, 2.56mmol) in THF (4 mL) and ethanol (4 mL) was added NaBH₄ (290 mg, 7.68mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. Thereaction was quenched with NH₄Cl, and the mixture was concentrated undervacuo. The residue was purified by silica gel chromatography (petroleumether:ethyl acetate=1/0 to 1/1) to give(5-methyl-1,2,4-oxadiazol-3-yl)methanol (250 mg).

Preparation of 5-methyl-1,2,4-oxadiazole-3-carbaldehyde

A solution of (5-methyl-1,2,4-oxadiazol-3-yl)methanol (250 mg, 2.19mmol) and Dess-Martin periodinane (1.39 g, 3.29 mmol) in dichloromethane(5 mL) was stirred at room temperature for 12 hours. The mixture wasfiltered and the filtrate was concentrated under vacuo to give5-methyl-1,2,4-oxadiazole-3-carbaldehyde (300 mg).

Preparation of methyl (tert-butoxycarbonyl)glycinate

To a solution of methyl glycinate (20 g, 159.30 mmol) in dioxane (120mL) and water (80 mL) was added Na₂CO₃ (33.77 g, 318.60 mmol) at 0° C.,Boc₂O (43.9 mL, 191 mmol) was added dropwise at room temperature. Themixture was stirred at room temperature for 18 h. The mixture wasconcentrated, water (200 mL) was added and the mixture was extractedwith ethyl acetate (100 mL×3). The organic layer was washed with water(50 mL×2) and brine (50 mL×2), dried with anhydrous Na₂SO₄, filtered,concentrated to give methyl (tert-butoxycarbonyl)glycinate (30 g) whichwas used for next step directly.

Preparation of tert-butyl (2-hydrazinyl-2-oxoethyl)carbamate

A mixture of methyl (tert-butoxycarbonyl)glycinate (10 g, 52.9 mmol) andhydrazine hydrate (4.37 mL, 89.85 mmol) in methanol (60 mL) and water(15 mL) were stirred at room temperature for 48 hours. The mixture wasconcentrated to give tert-butyl (2-hydrazinyl-2-oxoethyl)carbamate (10g).

Preparation of tert-butyl ((1,3,4-oxadiazol-2-yl)methyl)carbamate

To a solution of tert-butyl (2-hydrazinyl-2-oxoethyl)carbamate (5.00 g,26.4 mmol) in trimethoxymethane (50 mL) was added4-methylbenzenesulfonic acid (45.5 mg, 0.26 mmol). The mixture wasstirred at 80° C. for 4 hour. The mixture was concentrated. The crudemixture was purified by flash chromatography with petroleum ether:ethylacetate=3:1 to give tert-butyl ((1,3,4-oxadiazol-2-yl)methyl)carbamate(850 mg).

Preparation of (1,3,4-oxadiazol-2-yl)methanamine hydrobromide

A solution of tert-butyl ((1,3,4-oxadiazol-2-yl)methyl)carbamate (450mg, 2.26 mmol, 1.00 eq) in 35% hydrobromic acid in acetic acid (5 mL)was stirred at room temperature for 2 hours. The mixture wasconcentrated to give (1,3,4-oxadiazol-2-yl)methanamine hydrobromide (406mg).

Preparation of methyl 1,2,4-oxadiazole-3-carboxylate

To a solution of ethyl 2-amino-2-(hydroxyimino)acetate (1.90 g, 14.4mmol) in triethoxymethane (9.58 mL, 57.5 mmol) was added BF₃.Et₂O (0.089mL, 0.72 mmol). The mixture was heated at 90° C. for 2 hours. Themixture was concentrated and the residue was dissolved indichloromethane (30 mL). The organic layer was washed with 2N HCl (aq)(20 mL), Saturated aqueous NaHCO₃ (20 mL), water (20 mL), brine (20 mL)and dried over Na₂SO₄, filtered and concentrated to give methyl1,2,4-oxadiazole-3-carboxylate (1.60 g).

Preparation of (1,2,4-oxadiazol-3-yl)methanol

To a cooled (0° C.) solution of methyl 1,2,4-oxadiazole-3-carboxylate(300 mg, 2.11 mmol) in ethanol (2 mL) and THF (2 mL) was added NaBH₄(239 mg, 6.33 mmol). The mixture was stirred at 0° C. for 1 hour.Saturated aqueous NH₄Cl (5 mL) was added, the mixture was concentratedand the residue was dissolved in 10% methanol in dichloromethane (20mL). The mixture was filtered and the filtrate was concentrated. Theresidue was purified by flash chromatography on silica gel (10%˜100%ethyl acetate in petroleum ether) to give (1,2,4-oxadiazol-3-yl)methanol(40 mg).

Preparation of 1,2,4-oxadiazole-3-carbaldehyde

To a cooled (0° C.) solution of (1,2,4-oxadiazol-3-yl)methanol (40 mg,0.40 mmol) in dichloromethane (5 mL) was added Dess-Martin periodinane(254 mg, 0.60 mmol). The mixture was stirred at room temperature for 1hour. The mixture was filtered and the filtrate was concentrated to give1,2,4-oxadiazole-3-carbaldehyde (39 mg).

Preparation of ethyl (5-methyl-1H-1,2,4-triazol-3-yl)methanol

To a mixture of ethyl 5-methyl-1H-1,2,4-triazole-3-carboxylate (200 mg,1.29 mmol) in THF (5 mL) was added LiAlH₄ (245 mg, 6.45 mmol) at 0° C.under N₂. The mixture was stirred at 30° C. for 1 hour. The mixture wasfiltrated and washed with methanol, concentrated in vacuo togive(5-methyl-1H-1,2,4-triazol-3-yl)methanol (350 mg).

Preparation of 5-methyl-1H-1,2,4-triazole-3-carbaldehyde

To a mixture of (5-methyl-1H-1,2,4-triazol-3-yl)methanol (350 mg, 3.09mmol) in dichloromethane (10 mL) and acetonitrile (10 mL) was addedDess-Martin periodinane (2.62 g, 6.19 mmol). The mixture was stirred at30° C. for 14 hours. The mixture was filtrated and washed with petroleumether and ethyl acetate and concentrated in vacuo togive5-methyl-1H-1,2,4-triazole-3-carbaldehyde (90 mg).

Preparation of 4-bromo-6-chloro-2-methylpyridin-3-amine

To an ice cold solution of 6-chloro-2-methylpyridin-3-amine (12 g, 84mmol) and AcOH (5.1 g, 84 mmol) in MeOH (198 g, 250 mL) was dropwiseadded bromine (13.5 g, 84 mmol). The resulting solution was stirred atice bath temperature overnight after which it was concentrated undervacuo. The obtained residue was dissolved in EtOAc and sequentiallywashed with saturated aqueous NaHCO₃ solution, 10% Na₂S₂O₃ aqueoussolution, brine and dried (Na₂SO₄). The solvent was removed under vacuoand the obtained crude material was purified by flash chromatography toafford 4-bromo-6-chloro-2-methylpyridin-3-amine (12.6 g). ¹H NMR (500MHz, Chloroform-d) δ 7.30 (s, 1H), 4.04 (brs, 2H), 2.46 (s, 3H).

Preparation of 7-bromo-5-chloro-1H-pyrazolo[4,3-b]pyridine

Isopentyl nitrite (3.97g, 33.9 mmol) was dropwise added to an ice coldsuspension of 4-bromo-6-chloro-2-methylpyridin-3-amine (5 g, 22.6 mmol),KOAc (4.43 g, 45.2 mmol) and AcOH (44.1 g, 734 mmol) in toluene (125 mL)under an inert atmosphere. A reflux condenser was inserted and thereaction mixture was heated at 30° C. over 4 h, after which most of thesolvent was removed under vacuo. The obtained residue was dissolved inethyl acetate and carefully washed with saturated aqueous NaHCO₃solution ensuring that pH 8-9 was obtained. The organic layer was washedwith brine, dried (Na₂SO₄) and concentrated to a crude material whichwas purified by flash chromatography (SiO₂) to deliver7-bromo-5-chloro-1H-pyrazolo[4,3-b]pyridine (2.3 g, 44% yield). ¹H NMR(500 MHz, Chloroform-d) δ 10.61 (brs, 1H), 8.35 (s, 1H), 7.60 (s, 1H)

Preparation of7-bromo-5-chloro-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridine

Diisopropyl azodicarboxylate (979 mg, 4.84 mmol) was dropwise added toan ice cold solution of 7-bromo-5-chloro-1H-pyrazolo[4,3-b]pyridine (250mg, 1.08 mmol), triphenylphosphine (1.27 g, 4.84 mmol) and oxetan-3-ol(319 mg, 4.30 mmol) in THF (10 mL) under an inert atmosphere. The icebath was allowed to warm to room temperature and stirring continued atroom temperature overnight. Most of the solvent was removed under vacuoand the crude material obtained was purified by flash chromatographydelivering 7-bromo-5-chloro-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridine(130 mg, 38% yield). ¹H NMR (Chloroform-d, 500 MHz) δ 8.31 (s, 1H), 7.56(s, 1H), 6.48 (p, J=6.9 Hz, 1H), 5.35 (t, J=6.5 Hz, 2H), 5.11 (t, J=7.1Hz, 2H).

Preparation of 3-(1,3-dioxolan-2-yl)pyridine

A solution of nicotinaldehyde (1 g, 9.34 mmol) in toluene (20 mL) wasadded toluene-4-sulfonic acid (1.93 g, 11 mmol) and stirred at 120° C.for 0.5 hour. Ethane-1,2-diol (637 mg, 10 mmol) was added and theresulting solution was stirred at 120° C. for 15 hours. The solution wasquenched with saturated aqueous NaHCO₃ (60 mL) and the aqueous phase wasextracted with DCM (30 mL×3). The combined organic phases were washedwith brine, dried with Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography (petroleum ether:ethylacetate=10:1 to 1:1) to give 3-(1,3-dioxolan-2-yl)pyridine (1.30 g, 92%yield). ¹H NMR (Chloroform-d, 400 MHz) δ 8.70 (d, J=2.0 Hz, 1H),8.61-8.60 (m, 1H), 7.79-7.77 (m, 1H), 7.32-7.29 (m, 1H), 5.84 (s, 1H),4.12-4.01 (m, 4H).

Preparation of 5-(1,3-dioxolan-2-yl)-1-methylpyridin-2(1H)-one

Dimethyl sulfate (1 g, 7.9 mmol) was slowly added dropwise to3-(1,3-dioxolan-2-yl)pyridine (1.20 g, 7.94 mmol) and stirred at 100° C.for 1 hour. The resulting solution was dissolved in H₂O (4 mL) and anaqueous solution of K₃[Fe(CN)₆] (6.27 g) in H₂O (24 mL) was added understirring and cooling. KOH (3.56 g) was added slowly, keeping thetemperature at 5° C. After adding DCM (12 mL), the solution was stirredat 20° C. for 0.5 hours, before additional portions of K₃[Fe(CN)₆] (3.1g) in H₂O (11 mL) and KOH (1.8 g) were added at 20° C. and stirred at20° C. for 12 hours. The aqueous phase was extracted with ethyl acetate(30 mL×3). The combined organic phases were washed with brine, driedwith Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by preparative HPLC to give5-(1,3-dioxolan-2-yl)-1-methylpyridin-2(1H)-one (250 mg).

Preparation of 1-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde

A solution of 5-(1,3-dioxolan-2-yl)-1-methylpyridin-2(1H)-one (250 mg,1.38 mmol) in 3% aqueous HCl (5 mL) was stirred at 100° C. for 3 hours.The solution was extracted with DCM (10 mL×3). The combined organicphases were washed with brine, dried with Na₂SO₄, filtered andconcentrated in vacuo to give1-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde (150 mg).

Preparation of 6-(difluoromethyl)nicotinaldehyde

To a solution of 5-bromo-2-(difluoromethyl)pyridine (400 mg, 1.92 mmol)in THF (2 mL) at 0° C. was added isopropylmagnesium chloride-lithiumchloride complex (1.3 M, 2.96 mL) dropwise. The reaction was allowed tostir at room temperature for 2 hours, then DMF (703 mg, 9.62 mmol) wasadded at 0° C. and the reaction was stirred for an additional 12 hoursat room temperature. The reaction was quenched with 2M HCl (aq) andbasified with 1M NaOH (aq) until pH=7. The organic layer was separatedand the aqueous layer was extracted with dichloromethane. The combinedorganic layers were dried over Na₂SO₄ and concentrated. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=1/0 to 10:1) to give 6-(difluoromethyl)nicotinaldehyde (130 mg).

Preparation of methyl 5-methoxypyrazine-2-carboxylate

To a solution of 5-methoxypyrazine-2-carboxylic acid (1 g, 6.49 mmol) inMeOH (20 mL) was added SOCl₂ (927 mg, 7.79 mmol) at 15° C. The mixturewas refluxed at 60° C. for 2 hours to give a brown solution. Thereaction mixture was concentrated under reduced pressure to give aresidue. The residue was diluted with dichloromethane (20 mL) and the pHwas adjusted to 8 by NaHCO₃ (aq, 50 mL). The mixture was extracted withdichloromethane (100 mL×3). The combined organic layers were washed withbrine (100 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give methyl 5-methoxypyrazine-2-carboxylate(1.02 g).

Preparation of (5-methoxypyrazin-2-yl)methanol

To a solution of methyl 5-methoxypyrazine-2-carboxylate (200 mg, 1.19mmol) in THF (0.1 mL) and MeOH (4 mL) was added NaBH₄ (225 mg, 5.95mmol). The mixture was stirred at 15° C. for 16 hours. The mixture wasquenched with water (5 mL), then diluted with further water (15 mL),extracted with ethyl acetate (2×25 mL) then 20 percent 2-propanol indichloromethane (25 mL). The combined organic extracts were dried overanhydrous Na₂SO₄, filtered and concentrated to give(5-methoxypyrazin-2-yl)methanol (122 mg).

Preparation of 5-methoxypyrazine-2-carbaldehyde

To a solution of (5-methoxypyrazin-2-yl)methanol (115 mg, 0.82 mmol) indichloromethane (3 mL) was added MnO₂ (714 mg, 8.21 mmol) at 15° C. Thereaction mixture was refluxed at 50° C. for 18 hours. The reactionmixture was cooled to 20° C., filtered through celite and washed withdichloromethane (100 ml). The filtrate was concentrated to afford5-methoxypyrazine-2-carbaldehyde (45 mg).

Preparation of 4-ethyloxazolidin-2-one

To a solution of 2-aminobutan-1-ol (1 g, 11.2 mmol), carbonyldiimidazole (2.18 g, 13.5 mmol) in THF (3 mL) was added Et₃N (1.14 g,11.2 mmol) under argon atmosphere. The reaction was stirred at roomtemperature for 12h. The mixture was concentrated and the residue waspurified by column chromatography (SiO₂, Petroleum ether:Ethylacetate=10:1 to 5:1) to give 4-ethyloxazolidin-2-one (800 mg).

Preparation of5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde

A solution of i-PrMgCl-LiCl (1.3 M, 3.6 mL) in THF was dropwise addedinto a mixture of5,7-dibromo-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine (1.3 g, 3.9mmol) in THF (25 mL) at 0° C. The mixture was stirred at roomtemperature for 30 min. Then the mixture was recooled to 0° C. and DMF(1.4 g, 19.5 mmol, 1.5 mL) was added and the resulting mixture wasstirred at room temperature for another 2.5 hours. NH₄Cl (aq. 2 mL) wasadded to quench the reaction, then water (20 mL) was added and themixture was extracted with ethyl acetate (20 mL×3). The combined organiclayer was washed with brine (10 mL), dried over Na₂SO₄ and concentrated.The crude mixture was purified by flash chromatography with petroleumether:ethyl acetate=30:1˜20:1 to give5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine -7-carbaldehyde(800 mg).

Preparation ofN-((5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)methyl)-5-methoxypyridin-3-amine

To a solution of5-bromo-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine-7-carbaldehyde (50mg, 0.18 mmol) in dioxane (3 mL) was added Ti(i-PrO)₄ (101 mg, 0.35mmol) and 5-methoxypyridin-3-amine (44 mg, 0.35 mmol). The mixture wasstirred at 80° C. for 14 hours. After the reaction mixture had cooled toroom temperature, EtOH (3 mL) was added followed by addition of NaBH₄(35 mg, 0.9 mmol). The mixture was stirred at room temperature for 15minutes. Water (0.5 mL) was added to quench the reaction at 0° C. Andthe resulting mixture was stirred at room temperature for 10 minutes,then filtered and the residue was washed with ethyl acetate (30 mL×3).The combined organic layers was dried and concentrated. The crudeproductN-[(5-bromo-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl)methyl]-5-methoxy-pyridin-3-amine(69 mg) was used into the next step without further purification.

N-((5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)methyl)-1-methyl-1H-1,2,4-triazol-3-aminewas prepared in similar manner from5-bromo-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine-7-carbaldehyde and1-methyl-1,2,4-triazol-3-amine.

Preparation of5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde

A mixture of5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde(0.56 g, 1.98 mmol), (2-ethoxy-3-pyridyl)boronic acid (497 mg, 2.98mmol), Pd(dppf)Cl₂ (145 mg, 0.2 mmol), Cs₂CO₃ (1.94 g, 5.95 mmol) indioxane (8 mL), water (2 mL) was stirred at 100° C. for 2 hours. Themixture was concentrated under reduced pressure. The residue wasextracted with ethyl acetate (30 mL×2). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=10:1 to 3:1)to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde(0.55 g).

Preparation of5-(2-ethoxypyridin-3-yl)-7-ethynyl-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine

A mixture of5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine-7-carbaldehyde(0.55 g, 1.70 mmol), 1-diazo-1-dimethoxyphosphoryl-propan-2-one (423 mg,2.20 mmol) and Cs₂CO₃ (1.66 g, 5.09 mmol) in MeOH (7 mL) was stirred atroom temperature for 2 hours. The mixture was concentrated under reducedpressure and extracted with DCM (20 mL×2). The combined organic layerswere washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give crude.5-(2-ethoxypyridin-3-yl)-7-ethynyl-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine(0.5 g).

Preparation of tert-butyl ((6-chloropyrazin-2-yl)methyl)carbamate

To a suspension of Raney-Ni (307 mg, 3.59 mmol,) in EtOH (20 mL) wasadded 6-chloropyrazine-2-carbonitrile (1.00 g, 7.17 mmol,) andtert-butoxycarbonyl tert-butyl carbonate (1.72 g, 7.88 mmol), then thereaction mixture was stirred at room temperature under H₂ (45 psi) for16 hours. The reaction mixture was filtered through celite and thefiltrate was concentrated under reduced pressure to give a residue. Theresidue was purified by flash silica gel chromatography (eluention with0˜10% Ethyl acetate/Petroleum ether gradient) to give tert-butylN-[(6-chloropyrazin-2-yl)methyl]carbamate (1.05 g).

Preparation of tert-butyl ((6-methoxypyrazin-2-yl)methyl)carbamate.

To an ice cold solution of tert-butylN-[(6-chloropyrazin-2-yl)methyl]carbamate (500 mg, 2.05 mmol,) in MeOH(10 mL) was added sodium methoxide (443 mg, 8.21 mmol), then thereaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was concentrated under reduced pressure. The residuewas diluted with water (100 mL) and extracted with ethyl acetate (100mL×3). The combined organic layers were washed with saturated aqueousNH₄Cl (100 mL×2), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified byflash silica gel chromatography (eluention with 0˜16% Ethylacetate/Petroleum ether) to give tert-butylN-[(6-methoxypyrazin-2-yl)methyl]carbamate (300 mg).

Preparation of (6-methoxypyrazin-2-yl)methanamine hydrochloride

A solution of tert-butyl N-[(6-methoxypyrazin-2-yl)methyl]carbamate (350mg, 1.46 mmol) in 4N HCl/dioxane (10 mL) was stirred at room temperaturefor 2 hours. The reaction mixture was concentrated under pressure togive a (6-methoxypyrazin-2-yl)methanamine hydrochloride. The crudeproduct was used directly without further purification.

The following compound was prepared in a similar manner:

(3-methoxypyrazin-2-yl)methanamine hydrochloride Preparation of(4-methoxy-3-pyridyl)methanamine

To a solution of 4-methoxypyridine-3-carbonitrile (200 mg, 1.49 mmol),25% ammonia in water (0.23 mL) and MeOH (5 mL) was added to Raney-Ni (30mg, 10%), the reaction mixture was stirred at room temperature for 4hours under a H₂ atmosphere (45 psi). The reaction mixture was filteredto remove the catalyst and the filter cake was washed with MeOH (10mL×3), the filtrate was concentrated under vacuo to give the crudeproduct (4-methoxy-3-pyridyl)methanamine (150 mg).

Preparation of 6-methylheptyl3-((5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thio)propanoate

A solution of5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine (150 mg,0.45 mmol), 6-methylheptyl 3-mercaptopropanoate (124 mg, 0.57 mmol),DIPEA (116 mg, 157 μL, 0.90 mmol) in NMP (2 mL) was stirred at rt underinert atmosphere over 15 minutes after which it was inserted in an oilbath at 50° C. and stirred overnight. Partitioned between water (25 mL)and a solution of pentane:ethyl acetate (1:1) (50 mL). The aq. layer wasextracted with fresh pentane:ethyl acetate (1:1) (20 mL). The combinedorg. layers were dried (Na₂SO₄) and concentrated. The crude matrial waspurified by flash chromatography with heptane:ethyl acetate 1:0 to 0:1to give 6-methylheptyl3-((5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thio)propanoate(194 mg).

Preparation of 6-methylheptyl3-((5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thio)propanoate

A suspension of 6-methylheptyl3-((5-bromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thio)propanoate(194 mg, 0.41 mmol),2-ethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (123mg, 0.50 mmol), PdCl₂(dppf)-CH₂Cl₂ (84 mg, 0.10 mmol), K₂CO₃ (85 mg,0.62 mmol) in 1,4-dioxane (5.5 mL) and water (0.3 mL) was degassed bybubbling nitrogen over 3 minutes and then stirred at 105° C. over 4hours. Most of the solvent was removed under vacuo. The obtained residuewas taken in ethyl acetate (25 mL) and filtered through a short pad ofCelite which was rinsed with ethyl acetate (10 mL×2). The combinedfiltrates were washed with brine (20 mL), dried (Na₂SO₄) andconcentrated. The crude material was purified by flash chromatographywith heptane:ethyl acetate 1:0 to 0:1 to give 6-methylheptyl3-((5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thio)propanoate(128 mg).

Preparation of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate

To a solution of prop-2-yn-1-ol (500 mg, 0.52 ml, 8.92 mmol) and ethyl2-nitroacetate (2.26 g, 1.88 ml, 16.95 mmol) in EtOH (15 ml) was addedDABCO (1.0 g, 8.92 mmol). The mixture was stirred at 80° C. for 72 hoursunder microwave irradiation. The mixture was concentrated and purifieddirectly by flash chromatography with heptane:ethyl acetate=1:0 to 0:1to give ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (400 mg).

Preparation of ethyl 5-(fluoromethyl)isoxazole-3-carboxylate

To a solution of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (50.0mg, 0.29 mmol) in DCM (2 mL) was added diethylaminosulfur trifluoride(70.6 mg, 0.06 ml, 0.44 mmol). The mixture was stirred at 40° C. for 1hour. Water (3 mL) was added and the mixture was extracted with ethylacetate (5 mL×3). The combined organic layers were washed with brine (5mL), dried over Na₂SO₄ and concentrated. The crude mixture was purifiedby flash chromatography with heptane:ethyl acetate=1:0 to 0:1 to giveethyl 5-(fluoromethyl)isoxazole-3-carboxylate (41.0 mg).

Preparation of (5-(fluoromethyl)isoxazol-3-yl)methanol

To a solution of ethyl 5-(fluoromethyl)isoxazole-3-carboxylate (50.0 mg,0.29 mmol) in THF (4 mL) at 0° C. was added lithium aluminum hydride(0.43 mL, 0.43 mmol, 1 M in THF). The mixture was stirred at 0° C. for 1hour. A half saturated solution of sodium potassium tartarate (5 mL) wasadded and the mixture was stirred vigorously for 30 minutes. The mixturewas then extracted with ethyl acetate (10 mL×3). The combined organiclayers were washed with brine (10 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by flash chromatographywith heptane:ethyl acetate=1:0 to 0:1 to give(5-(fluoromethyl)isoxazol-3-yl)methanol (29.0 mg).

Preparation of 3-(bromomethyl)-5-(fluoromethyl)isoxazole

To a solution of (5-(fluoromethyl)isoxazol-3-yl)methanol (17.0 mg 0.13mmol) in MeCN (2 mL) was added triphenylphosphine (68 mg, 0.26 mmol),2,6-lutidine (13.9 mg, 0.015 mL, 0.13 mmol) and CBr₄ (86 mg, 0.26 mmol).The reaction mixture was stirred at room temperature for 1 hour. Themixture was concentrated purified directly by flash chromatography withheptane:ethyl acetate=1:0 to 0:1 to give3-(bromomethyl)-5-(fluoromethyl)isoxazole (12 mg).

Preparation of ethyl 5-(bromomethyl)isoxazole-3-carboxylate

To a solution of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (50 mg,0.29 mmol) in MeCN (2 mL) was added triphenylphosphine (153 mg, 0.58mmol), 2,6-lutidine (31.3 mg, 0.034 mL, 0.29 mmol) and CBr₄ (194 mg,0.58 mmol). The reaction mixture was stirred at room temperature for 1.5hours. The mixture is concentrated and purified directly by flashchromatography with heptane:ethyl acetate=1:0 to 0:1 to give ethyl5-(bromomethyl)isoxazole-3-carboxylate (68 mg).

Preparation of (5-(bromomethyl)isoxazol-3-yl)methanol

To a solution of ethyl 5-(bromomethyl)isoxazole-3-carboxylate (26 mg,0.11 mmol) in THF (1 mL) at 0° C. was added diisopropyl aluminiumhydride (0.12 ml, 0.12 mmol, 1 M in THF). The mixture was stirred at 0°C. for 2 hours. Another 0.12 mmol of diisopropyl aluminium hydridesolution was added and the mixture was stirred for another hour. 3 dropsof 4M HCl (aq) was added followed by a half saturated solution of sodiumpotassium tartarate (5 mL). The mixture was stirred vigorously for 30minutes. The mixture was then extracted with ethyl acetate (10 mL×3).The combined organic layers were washed with brine (10 mL), dried overNa₂SO₄ and concentrated to give (5-(bromomethyl)isoxazol-3-yl)methanol(21.3 mg, 0.11 mmol).

Preparation of 5-(bromomethyl)-3-(fluoromethyl)isoxazole

To a solution of (5-(bromomethyl)isoxazol-3-yl)methanol in DCM (1 mL)was added diethylaminosulfur trifluoride (70.6 mg, 0.06 ml, 0.44 mmol).The mixture was stirred at 40° C. for 1 hour. Water (3 mL) was added andthe mixture was extracted with ethyl acetate (5 mL×3). The combinedorganic layers were washed with brine (5 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by flash chromatographywith heptane:ethyl acetate=1:0 to 0:1 to give5-(bromomethyl)-3-(fluoromethyl)isoxazole (7.0 mg, 0.04 mmol).

Preparation of methyl 1-(difluoromethyl)-1H-pyrazole-4-carboxylate

To a solution of 1-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (100mg, 0.62 mmol) in DCM (4 mL) was added (diazomethyl)trimethylsilane(0.62 mL, 1.23 mmol, 2 M in hexane). The mixture was stirred at roomtemperature for 2 hours. Acetic acid (0.2 mL) was added and the mixturewas co-evaporated with toluene (2×20 mL) to give methyl1-(difluoromethyl)-1H-pyrazole-4-carboxylate (99.0 mg, 0.56 mmol).

Preparation of (1-(difluoromethyl)-1H-pyrazol-4-yl)methanol

To a solution of methyl 1-(difluoromethyl)-1H-pyrazole-4-carboxylate(120 mg, 0.68 mmol) in THF (4 mL) at 0° C. was added lithium aluminumhydride (1.0 mL, 1.0 mmol, 1 M in THF). The mixture was stirred at 0° C.for 1 hour. A half saturated solution of sodium potassium tartarate (5mL) was added and the mixture was stirred vigorously for 30 minutes. Themixture was then extracted with ethyl acetate (10 mL×3). The combinedorganic layers were washed with brine (10 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by flash chromatographywith heptane:ethyl acetate=1:0 to 0:1 to give(1-(difluoromethyl)-1H-pyrazol-4-yl)methanol (101 mg, 0.68 mmol).

Preparation of 4-(bromomethyl)-1-(difluoromethyl)-1H-pyrazole

To a solution of (1-(difluoromethyl)-1H-pyrazol-4-yl)methanol (30 mg,0.20 mmol) in MeCN (1.5 mL) was added triphenylphosphine (106 mg, 0.41mmol), 2,6-lutidine (21.7 mg, 23.6 μl, 0.20 mmol) and CBr₄ (134 mg, 0.41mmol). The reaction mixture was stirred at room temperature for 1 hour.The mixture is concentrated and purified directly by flashchromatography with heptane:ethyl acetate=1:0 to 0:1 to give4-(bromomethyl)-1-(difluoromethyl)-1H-pyrazole (29 mg).

Preparation ofN-((1-(difluoromethyl)-1H-pyrazol-4-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

To a suspension of NaH (3.79 mg, 0.095 mmol, 60% w/w) in THF (1 mL) at0° C. was added5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(20.5 mg, 0.05 mmol). The mixture was stirred at 0° C. for 15 minutesbefore 4-(bromomethyl)-1-(difluoromethyl)-1H-pyrazole (10 mg, 0.05 mmol)in THF (1 mL) was added. The reaction mixture was slowly allowed toreach room temperature and stirred for 2 hours. Water (5 mL) was addedand the mixture was extracted with ethyl acetate (5 mL×3). The combinedorganic layers were washed with brine (10 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by flash chromatographywith heptane:ethyl acetate=1:0 to 0:1 to giveN-((1-(difluoromethyl)-1H-pyrazol-4-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(23 mg, 0.04 mmol).

The following examples were prepared in a similar manner:

5-(2-ethoxypyridin-3-yl)-N-((5-(fluoromethyl)isoxazol-3-yl)methyl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 3-(bromomethyl)-5-(fluoromethyl)isoxazole.

5-(2-ethoxypyridin-3-yl)-N-((3-(fluoromethyl)isoxazol-5-yl)methyl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-(bromomethyl)-3-(fluoromethyl)isoxazole.

Preparation of (2-oxo-1,2-dihydropyridin-3-yl)boronic acid

To a solution of 3-bromopyridin-2(1H)-one (3.3 g, 19 mmol) in THF (200mL) cooled to −78° C., TMEDA (tetramethylethylenediamine) (6.6 g, 57mmol) was added dropwise over 15 minutes followed by addition of n-BuLi(in hexane, 2.5 M, 23 mL). The resulting mixture was stirred for 15 minat −78° C. and then warmed to room temperature. The reaction mixture wascooled to 0° C., and trimethyl borate (3.9 g, 38 mmol) was addeddropwise over 30 minutes. After the addition was complete, the reactionmixture was warmed to room temperature and was stirred for 15 hours. Themixture was then cooled to 0° C. and a small amount of ice was addedfollowed by HCl (aq. 100 mL, 2M). The THF was removed under reducedpressure, and the aqueous solution was washed twice with dichloromethane(50 mL×2). Concentrated aqueous NaOH was added slowly until pH=5 wasattained and a precipitate formed. The mixture was cooled to 0° C. andstirred for 10 minutes. The solid was collected by filtration, washedwith cold water, and dried under vacuum to afford(2-oxo-1,2-dihydropyridin-3-yl)boronic acid.

Preparation of 2-(trifluoromethyl)pyridine-3-carbonitrile.

To 3-bromo-2-(trifluoromethyl)pyridine (1 g, 4.42 mmol) in NMP (10 mL)was added Zn(CN)₂ (572 mg, 4.87 mmol,) and Pd(PPh₃)₄ (1 g, 0.885 mmol,),then the reaction mixture was stirred at 140° C. for 1 hour by microwaveheating. The reaction mixture was cooled to room temperature, filteredthrough celite and washed with ethyl acetate (100 mL). The reactionmixture was extracted with ethyl acetate (100 mL×2) and the organiclayers were washed with water (100×3 mL), brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by flash chromatography onsilica gel (petroleum ether/ethyl acetate) to give 2-(trifluoromethyl)pyridine-3-carbonitrile.

Preparation of (2-(trifluoromethyl) pyridin-3-yl)methanamine.

To a solution of Raney-Ni (50 mg, 0.581 mmol) in MeOH (20 mL) was added2-(trifluoromethyl)pyridine-3-carbonitrile (500 mg, 2.91 mmol) andNH₃.water (6 M, 5 mL), then the reaction mixture was stirred at 30° C.for 2 hours. The reaction mixture was concentrated under reducedpressure to give a residue. To the residue was added HCl (2M, 2 mL) andwater (10 mL). The resulting solution was lyophilized. The crude productwas used for next step without further purification.

Preparation of tert-butyl ((5-methoxypyrimidin-2-yl)methyl)carbamate

A mixture of 5-methoxypyrimidine-2-carbonitrile (100 mg, 0.74 mmol) andBoc₂O (194 mg, 0.89 mmol) and MeOH (5 mL) was added to Raney-Ni (30 mg,10%), the reaction mixture was stirred at room temperature for 2 hoursunder a H₂ atmosphere (45 psi). The reaction mixture was filtered toremove the catalyst and the filter cake was washed with MeOH (10 mL×3),and the filtrate was concentrated under vacuum. The crude product waspurified by flash chromatography on silica gel (0˜10% ethyl acetate inpetroleum ether) to give tert-butyl((5-methoxypyrimidin-2-yl)methyl)carbamate.

Preparation of (5-methoxypyrimidin-2-yl)methanamine hydrochloride

A mixture of tert-butyl ((5-methoxypyrimidin-2-yl)methyl)carbamate (100mg, 0.42 mmol) and dichloromethane (5 mL) and HCl/dioxane (4 M, 2 mL)was stirred at room temperature for 0.5 hour. Water (10 mL) was added tothe reaction mixture and the solution was concentrated under vacuum toremove the organic phase and the aqueous phase was lyophilized to givethe crude product. The crude product(5-methoxypyrimidin-2-yl)methanamine was obtained.

Preparation of 4-methoxypyrimidine-2-carbonitrile

2-chloro-4-methoxy-pyrimidine (600 mg, 4.15 mmol) and Zn(CN)₂ (292 mg,2.49 mmol) and Pd(dppf)Cl₂ (607 mg, 0.83 mmol) were taken up into amicrowave tube in NMP (3 mL). The sealed tube was heated at 140° C. for1 hour under microwave irradiation. The reaction mixture was cooled toroom temperature, filtered through celite and washed with ethyl acetate(20 mL). The reaction mixture was extracted with ethyl acetate (20 mL×3)and the organic layers were washed with water (20×3 mL), brine (20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate) to give4-methoxypyrimidine-2-carbonitrile.

Preparation of tert-butyl N-[(4-methoxypyrimidin-2-yl)methyl]carbamate

To a solution of Raney-Ni (25 mg, 0.296 mmol) in EtOH (5 mL) was added4-methoxypyrimidine-2-carbonitrile (200 mg, 1.48 mmol) and Boc₂O (355mg, 1.63 mmol, 0.374 mL) under N2, then the reaction mixture was stirredat room temperature under H₂ (45 psi) for 2 hours. The reaction mixturewas filtered through celite and concentrated under reduced pressure togive a residue. The residue was purified by flash chromatography onsilica gel (petroleum ether/ethyl acetate) to give tert-butylN-[(4-methoxypyrimidin-2-yl)methyl]carbamate.

Preparation of (4-methoxypyrimidin-2-yl)methanamine hydrobromide

A solution of tert-butyl N-[(4-methoxypyrimidin-2-yl)methyl]carbamate(100 mg, 0.418 mmol) in HBr/water (3 mL) was stirred at room temperaturefor 1 hour. The reaction mixture was concentrated under reduced pressureto give a residue. The crude product was used in the next step withoutfurther purification.

Preparation of 6-methoxypyrimidine-4-carbonitrile

To a solution of 4-chloro-6-methoxy-pyrimidine (1 g, 6.92 mmol) in DMF(10 mL) was added Pd(PPh₃)₄ (2 g, 1.38 mmol) and Zn(CN)₂ (487 mg, 4.15mmol). The reaction mixture was stirred at 80° C. for 16 hours. Thereaction mixture was cooled to room temperature, filtered through celiteand washed with dichloromethane (100 mL). The reaction mixture wasextracted with dichloromethane (100 mL×3) and the organic layers werewashed with water (100×3mL) and brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by flash chromatography on silica gel(petroleum ether/ethyl acetate) to give6-methoxypyrimidine-4-carbonitrile.

Preparation of tert-butyl N-((6-methoxypyrimidin-4-yl)methyl)carbamate

To a solution of Raney-Ni (25 mg, 0.296 mmol) in EtOH (5 mL) was added6-methoxypyrimidine-4-carbonitrile (200 mg, 1.48 mmol) and Boc₂O (355mg, 1.63 mmol, 0.374 mL), then the reaction mixture was stirred at roomtemperature under H₂ (45psi) for 2 hours. The reaction mixture wasfiltered through celite and washed with EtOH (20 mL×2), the filtratedwas concentrated under reduced pressure to give a residue. The residuewas purified by flash chromatography on silica gel (petroleumether/ethyl acetate) to give tert-butylN-[(6-methoxypyrimidin-4-yl)methyl]carbamate.

Preparation of (6-methoxypyrimidin-4-yl)methanamine

A solution of tert-butyl N-[(6-methoxypyrimidin-4-yl)methyl]carbamate(240 mg, 1.00 mmol) in HCl/dioxane (10 mL) was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated underreduced pressure to give a residue. The residue was used in the nextstep without further purification.

Preparation of 3-bromopicolinaldehyde

To a solution of 2,3-dibromopyridine (5 g, 21.11 mmol) in toluene (50mL), t-BuLi (1.3 M, 19.50 mL) was dropwise added at −78° C. under N₂.The resulting mixture was stirred at −78° C. for 2 hours. DMF (1.9 g,25.33 mmol) was added dropwise at −78° C. The mixture was stirred at−78° C. for another 2 hours. The solution was quenched with NH₄Cl (aq. 1mL) at −78° C., and the mixture was concentrated under vacuum. Theresidue was purified by column chromatography on silica gel (Petroleumether/ethyl acetate=10/1 to 1/1) to afford 3-bromopicolinaldehyde.

Preparation of 3-bromo-2-(difluoromethyl)pyridine

To a solution of 3-bromopicolinaldehyde (1.3 g, 6.99 mmol) indichloromethane (30 mL) was added diethylaminosulfur trifluoride (2.25g, 13.98 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2hours under N₂. The solution was quenched with NaHCO₃ (aq. 15 mL) at 0°C. The aqueous phase was extracted with dichloromethane (10 mL×3). Thecombined organic phases were washed with brine (15 mL×1), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (petroleum ether/ethylacetate=1/0, 10/1) to afford 3-bromo-2-(difluoromethyl)pyridine

Preparation of 2-(difluoromethyl)nicotinonitrile

To a mixture of 3-bromo-2-(difluoromethyl)pyridine (600 mg, 2.88 mmol)and Zn(CN)₂ (373 mg, 3.17 mmol) in NMP (10 mL) was added Pd(PPh₃)₄ (333mg, 0.29 mmol). The reaction mixture was heated by microwave irradiationat 140° C. for 1 hour. The reaction mixture was poured into ethylacetate (50 mL). The mixture was washed with water (20 mL×3) and brine(15 mL×1), dried over Na₂SO₄ and filtered. The filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=1/0, 2/1) to afford2-(difluoromethyl)nicotinonitrile.

Preparation of tert-butyl((2-(difluoromethyl)pyridin-3-yl)methyl)carbamate

A mixture of 2-(difluoromethyl)nicotinonitrile (0.4 g, 2.60 mmol),(Boc)₂O (680 mg, 3.11 mmol) and Raney-Ni (22 mg, 0.26 mmol) in MeOH (20mL) was stirred at 30° C. for 2 hours under H₂ (40 psi). The mixture wasfiltered and the filtrate was concentrated under vacuum. The residue waspurified by silica gel chromatography (petroleum ether/ethylacetate=1/0, 3/1) to afford tert-butyl((2-(difluoromethyl)pyridin-3-yl)methyl)carbamate.

Preparation of (2-(difluoromethyl)pyridin-3-yl)methanamine hydrochloride

To a solution of tert-butyl((2-(difluoromethyl)pyridin-3-yl)methyl)carbamate (0.6 g, 2.32 mmol) indichloromethane (5 mL) was added HCl/dioxane (4M, 1 mL) at 0° C. Thereaction mixture was stirred at room temperature for 12 hours. Themixture was concentrated under vacuum to afford(2-(difluoromethyl)pyridin-3-yl)methanamine hydrochloride.

Preparation of 3-bromo-2-ethoxypyridine.

To a mixture of 3-bromo-2-chloropyridine (200 mg, 1 mmol) in EtOH (5 mL)was added t-BuOK (233 mg, 2 mmol). The mixture was stirred at 80° C. for12 hours. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give the crude product. The residue waspurified by flash chromatography on silica gel (0%“40% ethyl acetate inpetroleum ether) to afford 3-bromo-2-ethoxypyridine.

Preparation of 2-ethoxynicotinonitrile

To a solution of 3-bromo-2-ethoxy-pyridine (350 mg, 1.7 mmol) in NMP (2mL) was added Zn(CN)₂ (244 mg, 2.1 mmol) and Pd(dppf)Cl₂ (127 mg, 0.17mmol). The mixture was degassed with N₂ and heated at 140° C. undermicrowave irradiation for 1 hour. The mixture was cooled to roomtemperature and filtered through celite. The filtered cake was washedwith ethyl acetate (30 mL). The filtrate was washed with water (20 mL×2)and brine (20 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on silica gel (0%”20% ethylacetate in petroleum ether) to give 2-ethoxynicotinonitrile.

Preparation of tert-butyl ((2-ethoxypyridin-3-yl)methyl)carbamate

To a solution of Raney-Ni (24 mg, 0.28 mmol) in EtOH (5 mL) was added2-ethoxynicotinonitrile (210 mg, 1.4 mmol) and Boc₂O (371 mg, 1.7 mmol).The reaction mixture was stirred at room temperature under H₂ (45psi)for 2 hours. The reaction mixture was filtered through celite and washedwith EtOH (20 mL×2), then the filtrate was concentrated under reducedpressure to give a residue. The residue was purified by preperative HPLCto afford tert-butyl ((2-ethoxypyridin-3-yl)methyl)carbamate.

Preparation of (2-ethoxypyridin-3-yl)methanamine

A solution of tert-butyl ((2-ethoxypyridin-3-yl)methyl)carbamate (85 mg,0.34 mmol) in HCl/dioxane (4 M, 2 mL) was stirred at room temperaturefor 12 hours. The reaction mixture was concentrated under reducedpressure to afford 2-ethoxypyridin-3-yl)methanamine.

Preparation of 3-methoxypyridine-4-carbonitrile

3-chloropyridine-4-carbonitrile (250 mg, 1.80 mmol) was disolved in DMF(5 mL) and cooled to ice bath temperature. CH₃ONa (194.95 mg, 3.61 mmol)was added slowly and the reaction mixture was stirred at roomtemperature for 2 hours under a N₂ atmosphere. Water (20 mL) and ethylacetate (20 mL) were added to the reaction mixture. The aqueous phasewas extracted with ethyl acetate (20 mL×2). The organic phases werecombined and dried over anhydrous Na₂SO₄ (5 g), filtered andconcentrated under vacuum to give the product3-methoxypyridine-4-carbonitrile.

Preparation of (3-methoxy-4-pyridyl)methanamine

A mixture of 3-methoxypyridine-4-carbonitrile (200 mg, 1.49 mmol), NH₃in water (314 mg, 2.24 mmol, 25%) and Raney-Ni (30 mg) in MeOH (5 mL)was stirred at room temperature for 3 hours under a H2 atmosphere (45psi). The reaction mixture was filtered to remove the catalyst and thefilter cake was washed with MeOH (10 mL×3). The filtrate wasconcentrated under vacuum. The residue was dissolved in 1 M HCl (30 mL)and the solution was lyophilized to give(3-methoxy-4-pyridyl)methanamine hydrochloride (296 mg). A mixture of(3-methoxy-4-pyridyl)methanamine hydrochloride (100 mg, 0.57 mmol),Ambersep 900(OH) and iron exchange resin (150 mg) in MeCN (5 mL) wasstirred at room temperature for 0.5 hour. Universal indicator papershowed that pH of the solution was 9˜10. The reaction mixture wasfiltered to remove the resin and the filtrate was dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum to give(3-methoxy-4-pyridyl)methanamine.

Preparation of methyl 4-methoxypyrimidine-5-carboxylate

To a solution of 5-bromo-4-methoxypyrimidine (1 g, 5.29 mmol) in MeOH(20 mL) was added triethylamine (1.07 g, 10.58 mmol) and Pd(dppf)Cl₂(774 mg, 1.06 mmol). The suspension was degassed and purged with COseveral times. The mixture was heated at 80° C. under CO (50 psi) for 16hours. The mixture was filtered through celite and the filtrate wasconcentrated. The residue was purified by flash chromatography on silicagel (petroleum ether/ethyl acetate) to give methyl4-methoxypyrimidine-5-carboxylate.

Preparation of (4-methoxypyrimidin-5-yl)methanol

To a solution of methyl 4-methoxypyrimidine-5-carboxylate (250 mg, 1.49mmol) in THF (5 mL) was added LiAIH₄ (169 mg, 4.46 mmol) at −40° C. Themixture was stirred at −40° C. for 0.5 hour. Water (0.5 mL) and 15% NaOH(0.5 mL) were added. The mixture was extracted with ethyl acetate (20mL×2). The combined organic layer was washed with water (10 mL), driedover Na₂SO₄, filtered and concentrated. The residue was purified byflash chromatography on silica gel (petroleum ether/ethyl acetate) togive (4-methoxypyrimidin-5-yl)methanol.

Preparation of 5-(bromomethyl)-4-methoxypyrimidine

To a solution of (4-methoxypyrimidin-5-yl)methanol (50 mg, 0.36 mmol) indry dichloromethane (2 mL) was added PBr₃ (144 mg, 0.53 mmol) at 0° C.The mixture was stirred at 0° C. for 0.5 hour. The mixture wasconcentrated and ice-water (5 g) was added. The aqueous layer wasextracted with ethyl acetate (20 mL×2). The organic layer was dried overNa₂SO₄, filtered and concentrated to give5-(bromomethyl)-4-methoxypyrimidine (70 mg, crude).

Preparation of 3-bromo-2-(ethoxy-d₅)pyridine

NaH (60% dispersion in oil) (227 mg, 5.68 mmol) was suspended in THF (13ml) and cooled to ice bath temperature. A solution of ethanol-d₆ (296mg, 5.68 mmol) in THF (1.2 ml) was added dropwise. The resultingsuspension was stirred at ice bath temperature over 10 minutes afterwhich the cooling bath was removed and stirring continued for 0.5 hour.The resulting mixture was recooled to ice bath temperature and asolution of 3-bromo-2-fluoropyridine (500 mg, 2.84 mmol) in THF (1.2 ml)was added dropwise. After stirring for 15 minutes at ice bathtemperature the cooling was removed and stirring continued for 45minutes further at room temperature after which a reflux condenser wasinserted and the mixture was heated to 65° C. for 10 hours. The mixturewas recooled to ice bath temperature and quenched with a few drops ofwater. Most of the solvent was removed under vacuo. The obtained residuewas partioned between ethyl acetate (25 ml) and brine (10 ml). Theorganic layer was dried (Na₂SO₄) and concentrated. The residue waspurified by flash chromatography on silica gel (heptane/ethyl acetate)to give 3-bromo-2-(ethoxy-d₅)pyridine.

The following compounds were prepared in a similar manner:

3-bromo-2-(ethoxy-2,2,2-d₃)pyridine prepared from3-bromo-2-fluoropyridine and ethanol-2,2,2-d₃.

3-bromo-2-(ethoxy-1,1-d₂)pyridine prepared from 3-bromo-2-fluoropyridineand ethanol(1,1-d₂).

Preparation of2-(ethoxy-d₅)-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2yl)pyridine

A suspension of 3-bromo-2-(ethoxy-d₅)pyridine (152 mg, 0.73 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (242 mg,0.95 mmol), PdCl₂(dppf)-CH₂Cl₂ (120 mg, 0.15 mmol) and KOAc (216 mg,2.20 mmol) in 1,4-dioxane (2.5 ml) was degassed by bubbling N₂ throughthe suspension for approx. 3 minutes after which it was heated to 110°C. for 4.5 hours. The resulting suspension was diluted with ethylacetate (10 ml) and filtered through a short pad of Celite which wasrinsed with ethyl acetate (2×10 ml). Most of the solvent was removedunder vacuo. The obtained residue was taken into ethyl acetate (50 ml)and washed with brine (30 ml). The organic layer was dried (Na₂SO₄),filtered and concentrated. Purification by flash chromatography onsilica gel (elution from heptane to ethyl acetate) delivered2-(ethoxy-d₅)-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2yl)pyridine.

The following compounds were prepared in a similar manner:

2-(Ethoxy-2,2,2-d₃)-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2yl)pyridineprepared from 3-bromo-2-(ethoxy-2,2,2-d₃)pyridine.

2-(Ethoxy-1,1-d₂)-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2yl)pyridineprepared from 3-bromo-2-(ethoxy-1,1-d₂)pyridine.

Preparation of 2T-ethoxy-6-methyl-[2,3′-bipyridin]-5-amine

N₂ was bubbled through a mixture of 6-bromo-2-methylpyridin-3-amine (2.5g, 13.4 mmol),2-ethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5.0 g,20.1 mmol), PdCl₂(dppf)-CH₂Cl₂ (2.18 g, 2.67 mmol) and potassiumcarbonate (3.69 g, 26.7 mmol) in 1,4-dioxane (126 ml) and water (12 ml)for 10 minutes. A reflux condenser was inserted and the reaction mixturewas heated at 105° C. for 2.5 hours under an inert atmosphere afterwhich most of the solvent was removed under vacuo. The obtained residuewas taken into ethyl acetate (150 ml) and filtered through a short padof Celite which was rinsed with ethyl acetate (2×50 ml). Concentrationand purification by flash chromatography on silica gel (elution withheptane to heptane/dichloromethane (1:1) toheptane/dichloromethane/ethyl acetate (1:1:1.5)) delivered2′-ethoxy-6-methyl-[2,3′-bipyridin]-5-amine.

Preparation of 4-chloro-2′-ethoxy-6-methyl-[2,3′-bipyridin]-5-amine

A solution of 2′-ethoxy-6-methyl-[2,3′-bipyridin]-5-amine (7.40 g, 22.6mmol) and N-chloro succinimde (3.77 g, 28.2 mmol) in NMP (104 ml) wasstirred at room temperature for 15 minutes under an inert atmosphere. Areflux condenser was inserted and the solution was heated to 80° C. for3.5 hours after which it was allowed to reach room temperature andpartitioned between ethyl acetate (300 ml) and aqueous saturated NaHCO₃(3×200 ml). The combined aqueous layers were extracted with ethylacetate (50 ml). The combined organic layers were further washed withbrine (2×100 ml), dried (Na₂SO₄) and concentrated. The residue waspurified by flash chromatography on silica gel (heptane/ethyl acetate)to give 4-chloro-2′-ethoxy-6-methyl-[2,3′-bipyridin]-5-amine.

Preparation of7-chloro-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine

A suspension of 4-chloro-2′-ethoxy-6-methyl-[2,3′-bipyridin]-5-amine(4.01 g, 12.2 mmol) and potassium acetate (2.98 g, 30.4 mmol) in toluene(84 ml) and acetic acid (28 ml) was stirred at ice bath temperature for5 minutes under an inert atmosphere. Isopentyl nitrite (2.71 g, 23.11mmol) was added dropwise for 5 minutes. After stirring at ice bathtemperature over 10 minutes a reflux condenser was inserted and themixture was heated to 35° C. for 2.5 hours. Most of the solvent wasremoved under vacuo. The obtained residue was suspended in ethyl acetate(350m1) and washed with aqueous saturated NaHCO₃ (2×250 ml), brine (200ml), dried (Na₂SO₄) and concentrated. The residue was purified by flashchromatography on silica gel (heptane/ethyl acetate) to give7-chloro-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine.

Preparation of7-chloro-5-(2-ethoxypyridin-3-yl)-3-iodo-1H-pyrazolo[4,3-b]pyridine

A solution of7-chloro-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridine (1.0 g,3.64 mmol) and N-iodo succinimide (1.11 g, 4.91 mmol) in DMF (50.0 ml)was stirred at room temperature for 15 minutes under an inert atmosphereafter which a reflux condenser was inserted and stirring continued at35° C. for 11 hours. The solution was diluted with ethyl acetate (350ml) and washed with aqueous 10% Na₂S₂O₃ (100 ml), aqueous ½ saturatedNaHCO₃ (2×150 ml) and brine (50 ml). The organic layer was dried(Na₂SO₄) and concentrated to deliver7-chloro-5-(2-ethoxypyridin-3-yl)-3-iodo-1H-pyrazolo[4,3-b]pyridinewhich was used without further purification.

Preparation of7-chloro-5-(2-ethoxypyridin-3-yl)-3-iodo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine

A solution of diisopropyl azodicarboxylate (1.59 g, 7.86 mmol) in THF(3.0 ml) was dropwise added to an ice cold solution of7-chloro-5-(2-ethoxypyridin-3-yl)-3-iodo-1H-pyrazolo[4,3-b]pyridine (1.0g, 2.25 mmol), isopropanol (0.60 ml, 7.86 mmol) and triphenylphosphine(2.06 g, 7.86 mmol) in THF (25 ml) under an inert atmosphere. Afterstirring at ice bath temperature for 0.5 hours, the solution was allowedto reach room temperature and stirring continued for 4.5 hours. Most ofthe solvent was removed under vacuo and the obtained residue wasdissolved in ethyl acetate (150 ml) and washed with aqueous saturatedNaHCO₃ (150 ml), brine (100 ml), dried (Na₂SO₄) and concentrated.Purification by flash chromatography on silica gel (elution gradientfrom heptane to ethyl acetate) delivered7-chloro-5-(2-ethoxypyridin-3-yl)-3-iodo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

Preparation of7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-vinyl-1H-pyrazolo[4,3-b]pyridine

N₂ was bubbled through a suspension of7-chloro-5-(2-ethoxypyridin-3-yl)-3-iodo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine(10 mg, 0.023 mmol), tributyl(vinyl)stannane (9.9 μl, 0.034 mmol),bis(triphenylphosphine) palladiumI(II) dichloride (4 mg, 5.7 umol) in1,4-dioxane (0.30 ml) over 2 minutes. The mixture was stirred at 105° C.for 6.5 hours after which additional tributyl(vinyl)stannane (5.0 μl,0.017 mmol), bis(triphenylphosphine) palladiumI(II) dichloride (1.6 mg,2.3 μmol) and 1,4-dioxane (0.15 ml) were added. The mixture was degassedby bubbling N₂ over 2 minutes and reheated to 105° C. for 5 hours. Mostof the solvent was removed under vacuo. The obtained residue wasdissolved in ethyl acetate (20 ml), washed with brine (10 ml) and dried(Na₂SO₄). Concentration under vacuo delivered a residue which waspurified by flash chromatography on silica gel (elution gradient fromheptane to ethyl acetate) to deliver7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-vinyl-1H-pyrazolo[4,3-b]pyridine.

Preparation of1-(7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-3-yl)ethane-1,2-diol

A mixture of7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-vinyl-1H-pyrazolo[4,3-b]pyridine(10 mg, 0.03 mmol), osmium tetraoxide (as a 2.5 wt % in2-methyl-2-propanol) (37 ul, 2.9 umol), N-methylmorpholine (as a 50%aqueous solution) (14 mg, 0.06 mmol) in THF (0.29 ml) and water (0.10ml) was stirred at room temperature for 24 hours. The reaction wasquenched at room temperature with aqueous 10% Na₂S₂O₃ (0.2 ml) and theresulting mixture was stirred for 5 minutes, diluted with brine (0.3 ml)and extracted with ethyl acetate (2×5 ml). The combined organic layerswere dried (Na₂SO₄) and concentrated to deliver crude1-(7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-3-yl)ethane-1,2-diolwhich was used without further purification.

Preparation of7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carbaldehyde

A mixture of1-(7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-3-yl)ethane-1,2-diol(9.0 mg, 0.024 mmol) and sodium periodate (7.7 mg, 0.04 mmol) in THF(0.25 ml) and water (55 μl) was stirred at room temperature for 40minutes after which sodium periodate (10.0 mg, 0.05 mmol) and 3 drops ofwater were added. After stirring for further 15 minutes, the resultingsuspension was diluted with ethyl acetate (5 ml) and stirred for 3minutes. The mixture was filtered through a short pad of Celite whichwas rinsed with ethyl acetate (2×5 ml). The combined filtrates werewashed with brine (5 ml), dried (Na₂SO₄) and concentrated to deliver7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carbaldehydewhich was used without further purification.

Preparation of(7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-3-yl)methanol

NaBH₄ (2.0 mg, 0.05 mmol) was added to an ice cold solution of7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carbaldehyde(4.0 mg, 0.01 mmol) in methanol (0.1 ml) under an inert atmosphere.After stirring for 5 minutes at ice bath temperature the resultingsolution was allowed to reach room temperature and stirring continuedfor 1 hour Recooled to ice bath temperature and quenched with a fewdrops of water. Most of the solvent was removed under vacuo. Theobtained residue was partitioned between ethyl acetate (15 ml) and brine(10 ml). The aqueous layer was back-extracted with ethyl acetate (5 ml).The combined organic layers were dried (Na₂SO₄) and concentrated. Theresidue was purified by flash chromatography on silica gel(heptane/ethyl acetate) to give(7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-3-yl)methanol.

Preparation of7-chloro-5-(2-ethoxypyridin-3-yl)-3-(fluoromethyl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine

Diethylaminosulfur trifluoride (5 μl, 0.04 mmol) was added to an icecold solution of(7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-3-yl)methanol(4.0 mg, 0.01 mmol) in CHCl₃ (0.2 ml). The reaction vial was capped andthe solution was stirred at 0° C. for 5 minutes after which the coolingbath was removed and stirring continued at room temperature for 12hours. The solution was diluted with ethyl acetate (25 ml) and washedwith aqueous saturated NaHCO₃ (2×15 ml), brine (10 ml), dried (Na₂SO₄)and concentrated. The residue was purified by flash chromatography onsilica gel (heptane/ethyl acetate) to give7-chloro-5-(2-ethoxypyridin-3-yl)-3-(fluoromethyl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

Preparation of7-chloro-3-(difluoromethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine

A solution of7-chloro-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine-3-carbaldehyde(5.0 mg, 0.01 mmol) and diethylaminosulfur trifluoride (10 μl, 0.08mmol) in dichloromethane (0.15 ml) was stirred at room temperature for4.5 hours. under an inert atmosphere. The mixture was diluted with ethylacetate (20 ml) and washed with aqueous saturated NaHCO₃ (10 ml) andbrine (10 ml). The organic layer was dried (Na₂SO₄) and concentrated.The residue was purified by flash chromatography on silica gel(heptane/ethyl acetate) to give7-chloro-3-(difluoromethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

Preparation of (2-hydrazinylpyridin-3-yl)methanol

Hydrazine hydrate (2.09 g, 41.8 mmol) was added to(2-chloropyridin-3-yl)methanol (2 g, 13.9 mmol) in THF (15 mL). Thereaction mixture was stirred at 80° C. overnight. A fresh portion ofhydrazine hydrate (2.04 g, 40.8 mmol) was added. The reaction mixturewas stirred at 80° C. overnight, then at 90° C. for 2 days. The reactionmixture was mixed with 50 mL water. The mixture was extracted withTHF/ethyl acetate (1/1). The organic phase was washed with brine, driedover MgSO₄ and concentrated in vacuo to give(2-hydrazinylpyridin-3-yl)methanol. Used in the next step withoutfurther purification.

Preparation of [1,2,4]triazolo[4,3-a]pyridine-8-carbaldehyde

Trimethoxymethane (2.5 ml, 22.9 mmol) was added to(2-hydrazinylpyridin-3-yl)methanol (95 mg, 0.683 mmol). The reactionmixture was heated by microwave irradiation using the Biotage Initiatorinstrument (150° C. for 60 minutes). The reaction mixture wasconcentrated in vacuo to give8-((dimethoxymethoxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine. Used in thenext step without further purification. Hydrochloric acid (0.3 mL, 0.3mmol, 1 molar in water) was added to8-((dimethoxymethoxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine (40 mg,0.179 mmol) in methanol (0.3 mL). The reaction mixture was heated bymicrowave irradiation using the Biotage Initiator instrument (100° C.for 10 minutes). The reaction mixture was concentrated in vacuo to give[1,2,4]triazolo[4,3-a]pyridin-8-ylmethanol hydrochloride. Used in thenext step without further purification. To a solution of[1,2,4]triazolo[4,3-a]pyridin-8-ylmethanol hydrochloride (85 mg, 0.46mmol) in dichloromethane (3 mL) was added N,N-diisopropylethylamine (71mg, 0.55 mmol) and manganese(IV) oxide (119 mg, 1.37 mmol). The mixturewas stirred at 50° C. in a sealed vial for 24 hours. The reactionmixture is filtered and concentrated to give[1,2,4]triazolo[4,3-c]pyridine-8-carbaldehyde.

Preparation of 3-methyl-[1,2,4]triazolo[4,3-c]pyridine-8-carbaldehyde

3-Methyl-[1,2,4]triazolo[4,3-a]pyridine-8-carbaldehyde was prepared in asimilar way from (2-hydrazinylpyridin-3-yl)methanol and1,1,1-trimethoxyethane.

Preparation of imidazo[1,5-a]pyridin-8-ylmethanol

To a solution of ethyl imidazo[1,5-a]pyridine-8-carboxylate (2 g, 10.52mmol) in THF (20 mL) was added LiAlH₄ (798 mg, 21.0 mmol) with stirringat 0° C. The resulting suspension was stirred at 20° C. for 2 hours. Thereaction mixture was cooled to 0° C. and was quenched with water (2 mL),then diluted with ethyl acetate (200 mL). The resulting suspension wasfiltered through a pad of A1₂0₃ and concentrated. The residue waspurified by column silica gel chromatography (Gradient: 0⁻10%, MeOH indichloromethane) to give imidazo[1,5-a]pyridin-8-ylmethanol.

Preparation of imidazo[1,5-a]pyridine-8-carbaldehyde

A suspension of imidazo[1,5-a]pyridin-8-ylmethanol (200 mg, 1.35 mmol)and Dess-Martin periodinane (1.15 g, 2.70 mmol) in dichloromethane (5mL) was stirred at 20° C. for 2 hours. The reaction mixture was filteredthrough a pad of Al₂O₃, and concentrated. The residue was purified bycolumn silica gel chromatography (Gradient: 0˜5%, MeOH indichloromethane) to give imidazo[1,5-a]pyridine-8-carbaldehyde.

Preparation of 7-methylbenzo[d]oxazole

A mixture of 2-amino-6-methylphenol (0.4 g, 3.3 mmol) intriethoxymethane (4.8 g, 32 mmol) was stirred at 140° C. for 12 hours.The solution was concentrated and the residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=1/0 to3/1) to afford7-methylbenzo[d]oxazole.

Preparation of 7-(bromomethyl)benzo[d]oxazole

To a solution of 7-methylbenzo[d]oxazole (0.1 g, 0.75 mmol) in CCl₄ (2mL) was added benzoyl peroxide (18 mg, 0.075 mmol) and NBS (147 mg, 0.83mmol), then the reaction mixture was stirred at 85° C. for 2 hours. Themixture was concentrated and the residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=1/0 to 10/1) to afford7-(bromomethyl)benzo[d]oxazole.

Preparation of methyl 2-methylbenzo[d]oxazole-4-carboxylate

A solution of methyl 2-amino-3-hydroxybenzoate (1 g, 5.98 mmol) in1,1,1-triethoxyethane (17.7 g, 109 mmol) was heated at 120° C. for 16hours. The mixture was concentrated. The residue was purified by flashsilica gel chromatography (ethyl acetate/petroleum ether gradient 0˜30%)to afford methyl 2-methylbenzo[d]oxazole-4-carboxylate.

Preparation of (2-methylbenzo[d]oxazol-4-yl)methanol

A solution of methyl 2-methyl-1,3-benzoxazole-4-carboxylate (100 mg,0.52 mmol) in THF (5 mL) was stirred at −78° C., DIBAL-H (diisobutylaluminium hydride) (1 M in toluene, 2.1 mL) was added in portions. Theresulting mixture was stirred at −78° C. for 1 hour. The reactionmixture was quenched by addition of methanol (1 mL) at 25° C., stirredfor 45 min, and then water (1 mL), and a saturated solution of ammoniumchloride (2 mL) was added with vigorous stirring. The resultantinorganic precipitate was removed by filtration. The filtrate wasextracted with ethyl acetate (20 mL×2). The combined organic layers werewashed with water (20 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash silica gelchromatography (ethyl acetate/petroleum ether gradient 0˜30%) to afford(2-methylbenzo[d]oxazol-4-yl)methanol.

Preparation of 4-(chloromethyl)-2-methylbenzo[d]oxazole

To a solution of (2-methylbenzo[d]oxazol-4-yl)methanol (40 mg, 0.25mmol) in dichloromethane (2 mL) was added SOCl₂ (87 mg, 0.74 mmol)dropwise at 0° C. The mixture was stirred at 25° C. for 1 hour. Themixture was concentrated to afford4-(chloromethyl)-2-methylbenzo[d]oxazole which was used directly in thenext step.

Preparation of methyl 2-methylbenzo[d]oxazole-5-carboxylate

A solution of methyl 3-amino-4-hydroxybenzoate (2 g, 12 mmol) and TFA(1.5 mL) in 1,1,1-triethoxyethane (15 mL) was stirred at 30° C. for 2hours. The solution was concentrated and the residue was purified bysilica gel chromatography (petroleum ether/ethyl acetate=1/0 to 3/1) toafford methyl 2-methylbenzo[d]oxazole-5-carboxylate.

Preparation of (2-methylbenzo[d]oxazol-5-yl)methanol

A solution of methyl 2-methylbenzo[d]oxazole-5-carboxylate (0.5 g, 2.6mmol) in THF (5 mL) was stirred at −20° C. LiAlH₄ (119 mg, 3.1 mmol) wasadded in small portions. The resulting suspension was stirred for 1 hourat −20° C. The mixture was quenched with H₂O (0.2 mL), and NaOH (aq.15%, 0.2 mL), and H₂O (0.6 mL) was added at 0° C. Then anhydrous Na₂SO₄and THF (15 mL) were added and the mixture was stirred at 0° C. for 0.5hour. The mixture was filtered and the filtrate was concentrated. Theresidue was purified by column chromatography (silica gel, petroleumether/ethyl acetate=1/0 to 1:1) to afford(2-methylbenzo[d]oxazol-5-yl)methanol.

Preparation of 5-(chloromethyl)-2-methylbenzo[d]oxazole

To a solution of (2-methylbenzo[d]oxazol-5-yl)methanol (100 mg, 0.61mmol) in dichloromethane (5 mL) was added SOCl₂ (219 mg, 1.8 mmol) at 0°C. and the reaction mixture was stirred at 30° C. for 3 hours. Thesolution was concentrated. The crude product5-(chloromethyl)-2-methylbenzo[d]oxazole was used directly in the nextstep.

Preparation of 4-chloro-2-(chloromethyl)pyrimidine

The solution of 4-chloro-2-methylpyrimidine (3 g, 23.34 mmol),1-chloropyrrolidine-2,5-dione (9.35 g, 70.01 mmol) andazobisisobutyronitrile (766 mg, 4.67 mmol) in carbon tetrachloride (30mL) was sealed and stirred at 100° C. for 30 hours under a N₂atmosphere. The reaction mixture was cooled to 20° C. and concentrated.The crude mixture was purified by flash chromatography with petroleumether/ethyl acetate to give 4-chloro-2-(chloromethyl)pyrimidine.

Preparation ofN-((4-chloropyrimidin-2-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

To the solution of5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(400 mg, 0.93 mmol), 4-chloro-2-(chloromethyl)pyrimidine (302 mg, 1.85mmol) and Nal (347 mg, 2.32 mmol) in DMF (3 mL) was added t-BuOK (260mg, 2.32 mmol). The resulting solution was 90° C. for 15 hours. Water(10 mL) was added. The resulting mixture was extracted with ethylacetate (30 mL×3). The combined organic layers were washed with brine(20 mL), dried over Na₂SO₄, and concentrated. The residue was purifiedby preparative HPLC to giveN-((4-chloropyrimidin-2-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

Preparation of5-(2-ethoxypyridin-3-yl)-N-((4-hydrazinylpyrimidin-2-yl)methyl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

To a solution ofN-((4-chloropyrimidin-2-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(0.025 g, 0.045 mmol) in THF (1 mL) was added NH₂NH₂ (1 M, 1 mL, 1 mmol,solution in THF). The resulting solution was stirred at 20° C. for 15hours. The reaction mixture was concentrated to give crude5-(2-ethoxypyridin-3-yl)-N-((4-hydrazinylpyrimidin-2-yl)methyl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

Preparation ofN-([1,2,4]triazolo[4,3-c]pyrimidin-5-ylmethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

To a soution of5-(2-ethoxypyridin-3-yl)-N-((4-hydrazinylpyrimidin-2-yl)methyl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(crude used from previous step) in trimethyl orthoformate (2.5 mL, 23mmol) was stirred at 50° C. for 15 hours.

The reaction mixture was cooled to 20° C. and concentrated in vacuo. Thecrude mixture was purified by flash chromatography with petroleumether/ethyl acetate to giveN-([1,2,4]triazolo[4,3-c]pyrimidin-5-ylmethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

Preparation ofN-((4-aminopyrimidin-2-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

To a solution of5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxyphenyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine(200 mg, 0.46 mmol,) in DMF (3 mL) was added t-BuOK (156 mg, 1.39 mmol),NaI (209 mg, 1.39 mmol) and 2-(chloromethyl)pyrimidin-4-amine (133 mg,0.93 mmol). The mixture was heated at 100° C. for 16 hours. Water (5 mL)was added. The mixture was extracted with ethyl acetate (20 mL×2). Thecombined organic layer was washed with H₂O (20 mL×2), brine (20 mL),dried over Na₂SO₄, filtered and concentrated. The crude mixture waspurified by flash chromatography with petroleum ether/ethyl acetate togiveN-[(4-aminopyrimidin-2-yl)methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxyphenyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine.

Preparation of5-(2-ethoxypyridin-3-yl)-N-(imidazo[1,2-c]pyrimidin-5-ylmethyl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

To a solution ofN-[(4-aminopyrimidin-2-yl)methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxyphenyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine(50 mg, 0.09 mmol) in EtOH (4 mL) was added 2-chloroacetaldehyde (310mg,1.58 mmol) (40% in H₂O) and triethylamine (47 mg, 0.46 mmol). Themixture was heated at 85° C. for 16 hours. After cooling to roomtemperature the reaction mixture was concentrated. The residue wasdissolved in dichloromethane (20 mL) and washed with saturated sodiumbicarbonate solution (20 mL) and brine (20 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by flash chromatographywith petroleum ether/ethyl acetate to give5-(2-ethoxy-3-pyridyl)-N-(imidazo[1,2-c]pyrimidin-5-ylmethyl)-1-isopropyl-N-[(4-methoxyphenyl)methyl]-3-methylpyrazolo[4,3-b]pyridin-7-amine.

Preparation of 4-nitro-3-propoxypyridine 1-oxide

Na (109 mg, 4.74 mmol) was added to n-PrOH (5 mL) with stirring. Thesolution was stirred at 80° C. for 0.5 hour. The reaction mixture wascooled to 0° C. The resulting solution was added into another solutionof 3-fluoro-4-nitropyridine 1-oxide (0.5 g, 3.16 mmol) in n-PrOH (5 mL)with stirring. The resulting solution was stirred for 10 minutes. Thetemperature was raised to 25° C., and stirred for 10 minutes. Thepropanol was evaporated under reduced pressure. Then water (20 mL) wasadded into the residue. The mixture was extracted with ethyl acetate (30mL×3). The organic layers were washed brine (20 mL), dried over Na₂SO₄,and concentrated. The residue was purified by column silica gelchromatography (Gradient: 0˜10%, ethyl acetate in petroleum ether) togive 4-nitro-3-propoxypyridine 1-oxide.

Preparation of 4-bromo-3-propoxypyridine

To a solution of 4-nitro-3-propoxypyridine 1-oxide (560 mg, 2.83 mmol)in ethyl acetate (15 mL), a solution of phosphorus tribromide (7.65 g,28.3 mmol) in ethyl acetate (5 mL) was added dropwise at a rate to keepthe reaction temperature below 40° C. The mixture was stirred for 10minutes, then at 80° C. for 15 hours. The mixture was cooled to 20° C.and concentrated. The residue was poured into ice water (50 mL). Underice cooling, 2 M sodium hydroxide aqueous solution was added at a rateto keep the temperature at 20° C. to adjust the reaction system topH=10. The reaction mixture was extracted with ethyl acetate (50 mL×3),the organic layer was washed with saturated brine (20 mL), dried overanhydrous sodium sulfate and then concentrated. The residue was purifiedby flash column silica gel chromatography (Gradient: 0˜40%, ethylacetate in petroleum ether) to give 4-bromo-3-propoxypyridine.

Preparation of 4-bromo-3-ethoxypyridine

To a solution of 4-bromopyridin-3-ol (500 mg, 2.87 mmol) in DMF (10 mL)was added bromoethane (313 mg, 2.87 mmol) and K₂CO₃ (794 mg, 5.75 mmol).The mixture was heated at 60° C. for 16 hours. The mixture wasconcentrated. The residue was dissolved in ethyl acetate (20 mL) and H₂O(20 mL). The organic layer was washed with H₂O (20 mL×2), brine (20 mL),dried over Na₂SO₄, filtered and concentrated to give4-bromo-3-ethoxy-pyridine.

Preparation of3-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a solution of 4-bromo-3-ethoxy-pyridine (50 mg, 0.25 mmol) in dioxane(3 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis(1,3,2-dioxaborolane) (94 mg,0.37 mmol), Pd(dppf)Cl₂ (36 mg, 0.05 mmol) and KOAc (73 mg, 0.74 mmol).The mixture was bubbled with N₂ and heated at 100° C. for 16 hours. Themixture was cooled to 20° C. The solution of3-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (62 mg,crude) in dioxane (3 mL) was directly used in the next step.

Preparation of (3-propoxypyridin-4-yl)boronic acid

(3-propoxypyridin-4-yl)boronic acid was prepared in a similar way from4-bromo-3-propoxypyridine

Preparation of 3-chloro-6-ethoxypyridazine

A mixture of 3,6-dichloropyridazine (4 g, 26.85 mmol) and K₂CO₃ (5.57 g,40.28 mmol) in ethanol (60 mL) was stirred at 90° C. for 20 hours. Thereaction mixture was cooled to 20° C., solvent was removed byevaporation. The residue was diluted with saturated NH₄Cl aqueoussolution (40 mL), then the mixture was extracted with ethyl acetate (50mL×3). The organic layers were washed with brine (40 mL), dried overNa₂SO₄, and concentrated to give 3-chloro-6-ethoxy-pyridazine.

Preparation of 3-ethoxypyridazine

To a solution of 3-chloro-6-ethoxy-pyridazine (1 g, 6.31 mmol) andammonium formate (596 mg, 9.46 mmol) in EtOH (5 mL) was added Pd/C (10%Pd, 50% water, 0.01 g) under N₂. The mixture was stirred at 50° C. for 1hour. The reaction mixture was filtered and the filtrate wasconcentrated. The crude product was purified by silica gelchromatography (Gradient: 0100%, ethyl acetate in petroleum ether) togive 3-ethoxypyridazine.

Preparation of 3-ethoxy-4-(tributylstannyl)pyridazine

n-Butyllithium (2.5 M, 3.7 mL, in hexane) was slowly added to a solutionof 2,2,6,6-tetramethylpiperidine (1.31 g, 9.26 mmol) in diisopropylether (15 mL) at −30° C. under argon. The reaction mixture was stirredat 0° C. for 30 minutes before being cooled to −78° C. and a solution of3-ethoxypyridazine (0.5 g, 4.03 mmol) in diisopropyl ether (4 mL) wasslowly added. Tributylchlorostannane (1.86 g, 5.71 mmol) was then addedin 10 portions at the same temperature. After stirring at −78° C. for 45minutes, a mixture of diisopropyl ether and an aqueous saturatedsolution of ammonium chloride (15 mL/15 mL) was added and thetemperature was allowed to warm up to 20° C. Additional diisopropylether (300 mL) was then added to the mixture and the organic layer wasseparated, washed with aqueous saturated solution of ammonium chloride(30 mL), dried over MgSO₄, and the mixture was concentrated. The residuewas purified by flash silica gel chromatography (Gradient: 0˜50%, ethylacetate in petroleum ether) to give3-ethoxy-4-(tributylstannyl)pyridazine.

Preparation of 3-propoxy-4-(tributylstannyl)pyridazine

3-propoxy-4-(tributylstannyl)pyridazine was prepared in a similar wayfrom 3,6-dichloropyridazine and propan-1-ol

Preparation of 3-methoxy-4-(tributylstannyl)pyridazine

3-methoxy-4-(tributylstannyl)pyridazine was prepared in a similar wayfrom 3,6-dichloropyridazine and methanol.

Preparation of tert-butyl ((5-fluoropyrimidin-2-yl)methyl)carbamate

To a solution of 5-fluoropyrimidine-2-carbonitrile (1 g, 8.12 mmol) anddi-cert-butyl dicarbonate (2.13 g, 9.75 mmol) in MeOH (40 mL) was addedRaney Nickel (0.1 g) under N₂. The suspension was degassed under vacuumand purged with H₂ several times. The mixture was stirred under H₂ (50psi) at 20° C. for 15 hours. The mixture was filtered through a pad ofdiatomaceous earth and concentrated. The residue was purified by columnsilica gel chromatography (Gradient: 0˜15%, ethyl acetate in petroleumether) to give tert-butyl ((5-fluoropyrimidin-2-yl)methyl)carbamate.

Preparation of (5-fluoropyrimidin-2-yl)methanamine

A solution of tert-butyl ((5-fluoropyrimidin-2-yl)methyl)carbamate (1.5g, 6.6 mmol) in HCl/ethyl acetate (15 mL) was stirred at 25° C. for 30min. The reaction mixture was cooled to 20° C. and concentrated to give(5-fluoropyrimidin-2-yl)methanamine hydrochloride.

Preparation of of methyl 2-methylbenzo[d]oxazole-4-carboxylate

A solution of methyl 2-amino-3-hydroxybenzoate (1 g, 5.98 mmol) in1,1,1-triethoxyethane (17.7 g, 109 mmol) was heated at 120° C. for 16hours. The mixture was concentrated. The residue was purified by flashsilica gel chromatography (0˜30% ethyl acetate/petroleum ether gradient)to afford methyl 2-methylbenzo[d]oxazole-4-carboxylate.

Preparation of (2-methylbenzo[d]oxazol-4-yl)methanol

A solution of methyl 2-methyl-1,3-benzoxazole-4-carboxylate (100 mg,0.52 mmol) in THF (5 mL) was stirred at 0° C., DIBAL-H (diisobutylaluminiumhydride) (1 M in toluene, 2.09 mL) was added in portions andthe resulting mixture was stirred at −78° C. for 1 hour. The reactionmixture was quenched by addition methanol (1 mL) at 25° C. stirred over45 min, and then water (1 mL) and a saturated solution of ammoniumchloride (2 mL) were added with vigorous stirring and the resultantinorganic precipitate was removed by filtration. The filtrate wasextracted with ethyl acetate (20 mL×2). The combined organic layers werewashed with water (20 mL×2), dried with anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash silica gelchromatography (ethyl acetate/petroleum ether gradient 0˜30%) to afford(2-methylbenzo[d]oxazol-4-yl)methanol.

Preparation of 4-(chloromethyl)-2-methylbenzo[d]oxazole

To a solution of (2-methylbenzo[d]oxazol-4-yl)methanol (40 mg, 0.25mmol) in dichloromethane (2 mL) was added SOCl₂ (87 mg, 0.74 mmol)dropwise at 0° C. and the mixture was stirred at 25° C. for 1 hour. Themixture was concentrated to afford4-(chloromethyl)-2-methylbenzo[d]oxazole.

Preparation of5-(3-ethoxypyridin-4-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

To a solution of5-chloro-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(500 mg, 1.45 mmol) and5-chloro-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(542 mg, 2.17 mmol) in dioxane (8 mL) and H₂O (3 mL) was addedPd(dppf)Cl₂ (107 mg, 0.14 mmol) and Cs₂CO₃ (945 mg, 2.90 mmol). Themixture was bubbled with N₂ and heated at 100° C. under N₂ for 3 hours.The mixture was cooled to 20° C. and extracted with ethyl acetate (20mL×2). The combined organic layer was washed with H₂O (20 mL), brine (20mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The residue was purified by flash silica gel chromatography(ethyl acetate/petroleum ether gradient 0˜30%) to give5-(3-ethoxypyridin-4-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

Preparation of5-(3-ethoxypyridin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

A solution of5-(3-ethoxy-4-pyridyl)-1-isopropyl-N-[(4-methoxyphenyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine(650 mg, 1.51 mmol) in TFA (10 mL) was heated at 60° C. for 16 hours.The mixture was concentrated. H₂O (2 mL) was added to the residue. Themixture was adjusted to pH=7 by saturated aqueous NaHCO₃ and extractedwith ethyl acetate (20 mL×2). The combined organic layer was washed withH₂O (20 mL), brine (20 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash silica gelchromatography (ethyl acetate/petroleum ether gradient 10˜100%) to give5-(3-ethoxypyridin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

Preparation of5-bromo-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

To a mixture of5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine (1 g, 3mmol) and (4-methoxyphenyl)methanamine (494 mg, 3.6 mmol) in NMP (10 mL)was added CsF (1.4 g, 9 mmol,). The mixture was stirred at 100° C. for12 hours. The mixture was filtered. The mixture was added H₂O (5 mL) andextracted with ethyl acetate (20 mL). The combined organic phases werewashed with brine, dried with anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by Flash silica gelchromatography (0%“30% ethyl acetate in petroleum ether) to give5-bromo-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

Preparation of5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

A mixture of5-bromo-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(500 mg, 1.3 mmol), 3-ethoxy-4-(tributylstannyl)pyridazine (584 mg, 1.4mmol) and CuI (24 mg, 0.13 mmol) in DMF (5 mL) was subjected to threecycles of evacuation and backfilling with N₂. Pd(PPh₃)₄ (148 mg, 0.13mmol) was then added and the resulting mixture was subjected to threefurther cycles of evacuation and backfilling with N₂ before beingstirred at 100° C. for 12 hours. The reaction mixture was cooled to 25°C. and was partitioned between EtOAc (20 mL) and H₂O (20 mL). Theorganic phase was separated, washed with H₂O (10 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byFlash silica gel chromatography (0%˜50% ethyl acetate in petroleumether) to give5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

Preparation of5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

A solution of5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(820 mg, 1.9 mmol) in TFA (20 mL) was heated at 60° C. for 16 hours. Themixture was concentrated. H₂O (2 mL) was added to the residue. Themixture was adjusted to pH=7 by saturated aqueous NaHCO₃ and extractedwith ethyl acetate (20 mL×2). The combined organic layers were washedwith H₂O (20 mL), brine (20 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by Flash silica gelchromatography (0%˜50% ethyl acetate in petroleum ether) to give5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

Compounds of the Invention EXAMPLE 1a5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(3-methyl-[1,2,4]triazolo[4,3-c]pyridin-8-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

To a solution of5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(15 mg, 0.05 mmol) and3-methyl-[1,2,4]triazolo[4,3-a]pyridine-8-carbaldehyde (15.5 mg, 0.10mmol) in THF (0.4 mL) was added tetraethyl orthotitanate (65.9 mg, 0.29mmol). The mixture was stirred at 75° C. for 2 hours before beeingdiluted with ethanol (0.15 mL) and cooled to 0° C. Sodium borohydride(9.1 mg, 0.24 mmol) was added and the reaction mixture was stirred atroom temperature for 1 hour. Water (10 mL) was added and the mixture wasextracted with ethyl acetate (20 mL×3). The combined organic layers werewashed with brine (20 mL), dried over Na2SO₄ and concentrated. The crudemixture was purified by flash chromatography (silica gel, heptane:ethylacetate=1:0 to 0:1) to give5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(3-methyl-[1,2,4]triazolo[4,3-c]pyridin-8-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (600 MHz, Chloroform-d) δ 8.22 (dd, J=7.3, 2.0 Hz, 1H), 8.15 (dd,J=4.9, 2.0 Hz, 1H), 7.82 (d, J=7.0 Hz, 1H), 7.23 (dd, J=6.7, 1.1 Hz,1H), 7.19 (s, 1H), 7.00 (dd, J=7.4, 4.9 Hz, 1H), 6.85 (t, J=6.8 Hz, 1H),6.35 (t, J=6.0 Hz, 1H), 5.08 (hept, J=6.6 Hz, 1H), 4.93 (d, J=5.9 Hz,2H), 4.44 (q, J=7.0 Hz, 2H), 2.77 (s, 3H), 2.63 (s, 3H), 1.65 (d, J=6.5Hz, 6H), 1.35 (t, J=7.0 Hz, 3H). LC-MS: t_(R)=0.47 minutes (Method D),m/z=457.6 [M+H]⁺.

EXAMPLE 2aN-(2,1,3-benzothiadiazol-4-ylmethyl)-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand benzo[c][1,2,5]thiadiazole-4-carbaldehyde. ¹H NMR (600 MHz,Chloroform-d) δ 8.22 (dd, J=7.4, 2.0 Hz, 1H), 8.14 (dd, J=4.9, 2.0 Hz,1H), 7.97 (dd, J=7.8, 2.2 Hz, 1H), 7.61-7.57 (m, 2H), 7.23 (s, 1H), 6.99(dd, J=7.4, 4.9 Hz, 1H), 5.67 (t, J=5.9 Hz, 1H), 5.05 (d, J=5.9 Hz, 2H),4.95 (hept, J=6.6 Hz, 1H), 4.36 (q, J=7.0 Hz, 2H), 2.64 (s, 3H), 1.64(d, J=6.5 Hz, 6H), 1.24 (t, J=7.0 Hz, 3H). LC-MS: t_(R)=0.65 minutes(Method D), m/z=460.5 [M+H]⁺.

EXAMPLE 3a5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-([1,2,4]triazolo[4,3-c]pyridin-8-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand [1,2,4]triazolo[4,3-a]pyridine-8-carbaldehyde. ¹H NMR (600 MHz,Chloroform-d) δ 8.86 (s, 1H), 8.22 (dd, J=7.4, 2.0 Hz, 1H), 8.15 (dd,J=4.9, 2.0 Hz, 1H), 8.09 (dd, J=6.9, 1.0 Hz, 1H), 7.27 (dd, J=6.8, 1.1Hz, 1H), 7.19 (s, 1H), 7.00 (dd, J=7.4, 4.9 Hz, 1H), 6.87 (t, J=6.8 Hz,1H), 6.26 (t, J=6.0 Hz, 1H), 5.07 (hept, J=6.6 Hz, 1H), 4.97 (d, J=5.9Hz, 2H), 4.42 (q, J=7.0 Hz, 2H), 2.63 (s, 3H), 1.65 (d, J=6.5 Hz, 6H),1.33 (t, J=7.0 Hz, 3H). LC-MS: t_(R)=0.57 minutes (Method D), m/z=443.6[M+H]⁺.

EXAMPLE 4a5-(2-ethoxy-3-pyridyl)-N-(imidazo[1,2-a]pyridin-8-ylmethyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand imidazo[1,2-a]pyridine-8-carbaldehyde. ¹H NMR (600 MHz,Chloroform-d) δ 8.23 (dd, J=7.3, 2.0 Hz, 1H), 8.16 (dd, J=4.9, 2.0 Hz,1H), 8.11 (dd, J=6.8, 1.1 Hz, 1H), 7.64-7.63 (m, 2H), 7.22 (s, 1H), 7.17(dd, J=6.8, 1.1 Hz, 1H), 7.01 (dd, J=7.4, 4.9 Hz, 1H), 6.87 (t, J=5.7Hz, 1H), 6.80 (t, J=6.8 Hz, 1H), 5.11 (hept, J=6.5 Hz, 1H), 4.86 (d,J=5.6 Hz, 2H), 4.45 (q, J=7.0 Hz, 2H), 2.63 (s, 3H), 1.62 (d, J=6.5 Hz,6H), 1.37 (t, J=7.0 Hz, 3H). LC-MS: t_(R)=0.49 minutes (Method D),m/z=442.5 [M+H]⁺.

EXAMPLE 5a5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrazolo[1,5-a]pyridin-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand pyrazolo[1,5-a]pyridine-4-carbaldehyde. ¹H NMR (600 MHz,Chloroform-d) δ 8.48 (d, J=6.9 Hz, 1H), 8.27 (dd, J=7.4, 2.0 Hz, 1H),8.14 (dd, J=4.9, 2.0 Hz, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.20 (s, 1H), 7.17(dd, J=6.9, 1.1 Hz, 1H), 7.00 (dd, J=7.4, 4.9 Hz, 1H), 6.78 (t, J=6.9Hz, 1H), 6.61 (dd, J=2.3, 0.9 Hz, 1H), 4.85 (t, J=5.4 Hz, 1H), 4.80(hept, J=6.6 Hz, 1H), 4.75 (d, J=5.3 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H),2.66 (s, 3H), 1.61 (d, J=6.5 Hz, 6H), 1.17 (t, J=7.0 Hz, 3H). LC-MS:t_(R)=0.52 minutes (Method D), m/z=442.5 [M+H]⁺.

EXAMPLE 6a5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-([1,2,4]triazolo[1,5-a]pyridin-5-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand [1,2,4]triazolo[1,5-a]pyridine-5-carbaldehyde. ¹H NMR (600 MHz,Chloroform-d) δ 8.43 (s, 1H), 8.24 (dd, J=7.4, 2.0 Hz, 1H), 8.15 (dd,J=4.9, 2.0 Hz, 1H), 7.77 (dd, J=9.0, 1.1 Hz, 1H), 7.54 (dd, J=8.9, 7.1Hz, 1H), 7.24 (s, 1H), 7.12 (dd, J=7.0, 1.1 Hz, 1H), 7.00 (dd, J=7.4,4.9 Hz, 1H), 5.92 (t, J=6.4 Hz, 1H), 5.06 (d, J=6.3 Hz, 2H), 4.95 (hept,J=6.6 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 2.63 (s, 3H), 1.64 (d, J=6.7 Hz,6H), 1.25 (t, J=7.0 Hz, 3H). LC-MS: t_(R)=0.61 minutes (Method D),m/z=443.6 [M+H]⁺.

EXAMPLE 7a5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-methyl-[1,2,4]triazolo[1,5-a]pyridine-5-carbaldehyde. ¹H NMR (600MHz, Chloroform-d) δ 8.22 (dd, J=7.4, 2.0 Hz, 1H), 8.16 (dd, J=4.9, 2.0Hz, 1H), 7.63 (dd, J=8.9, 1.2 Hz, 1H), 7.47 (dd, J=8.9, 7.0 Hz, 1H),7.23 (s, 1H), 7.02 (dd, J=7.2, 1.1 Hz, 1H), 7.00 (dd, J=7.4, 4.9 Hz,1H), 6.08 (t, J=6.4 Hz, 1H), 5.02-4.94 (m, 3H), 4.42 (q, J=7.0 Hz, 2H),2.64 (s, 3H), 2.62 (s, 3H), 1.64 (d, J=6.6 Hz, 6H), 1.30 (t, J=7.0 Hz,3H). LC-MS: t_(R)=0.51 minutes (Method D), m/z=457.7 [M+H]⁺.

EXAMPLE 8a5-(2-ethoxy-3-pyridyl)-N-(imidazo[1,5-a]pyridin-8-ylmethyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from6-(2-ethoxy-3-pyridyl)-3-isopropyl-1-methyl-pyrazolo[3,4-b]pyridin-4-amineand imidazo[1,5-a]pyridine-8-carbaldehyde. ¹H NMR (400 MHz,Chloroform-d) δ 8.27 (dd, J=1.6, 7.6 Hz, 1H), 8.21 (s, 1H), 8.14 (dd,J=1.6, 4.8 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.20 (s, 1H),7.00 (dd, J=4.8, 7.2 Hz, 1H), 6.79 (d, J=6.4 Hz, 1H), 6.63-6.52 (m, 1H),4.91 (br s, 1H), 4.88-4.78 (m, 1H), 4.73 (d, J=5.2 Hz, 2H), 4.32 (q,J=6.8 Hz, 2H), 2.66 (s, 3H), 1.63 (d, J=6.4 Hz, 6H), 1.20 (t, J=6.8 Hz,3H). LC-MS: t_(R)=1.23 min (Method A, m/z=442.1 [M+H]⁺

EXAMPLE 9aN-(1,3-benzoxazol-7-ylmethyl)-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

NaH (46 mg, 1.2 mmol, 60% dispersion in mineral oil) was added to asolution of5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(250 mg, 0.58 mmol) in DMF (10 mL) at 0° C. After stirring the mixtureat 30° C. for 0.5 hour, a solution of 7-(bromomethyl)benzo[d]oxazole(246 mg, 1.2 mmol) in DMF (5 mL) was added at 0° C. The solution wasstirred at 0° C. for 0.5 hour. The solution was quenched with NH₄Cl(saturated aqueous 0.5 mL) and concentrated. The residue was purified bysilica gel chromatography (petroleum ether/ethyl acetate=1/0 to 3/1) toaffordN-(benzo[d]oxazol-7-ylmethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.A solution ofN-(benzo[d]oxazol-7-ylmethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(100 mg, 0.18 mmol) in TFA (5 mL) was stirred at 30° C. for 1 hour. Thesolution was added drop-wise to TEA (30 ml) at 0° C., and stirred at 0°C. for 0.5 hour. The mixture was concentrated. The residue was dilutedwith ethyl acetate (60 mL) and washed with water (20 mL×3), brine (15mL), dried with anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified by column chromatography (SiO₂, petroleum ether/ethylacetate=1/0 to 1:1) to affordN-(1,3-benzoxazol-7-ylmethyl)-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (CDCl₃ 400 MHz): δ=8.23 (d, J=7.2 Hz, 1H), 8.18-8.13 (m, 2H),7.79 (d, J=7.6 Hz, 1H), 7.48-7.39 (m, 2H), 7.23 (s, 1H), 7.01 (dd,J=6.8, 4.0 Hz, 1H), 5.01 (br. s, 1H), 4.94-4.82 (m, 3H), 4.37 (q, J=6.8Hz, 2H), 2.66 (s, 3H), 1.64 (d, J=6.0 Hz, 6H), 1.27 (t, J=6.8 Hz, 3H).LC-MS: t_(R)=1.82 minutes (Method L), m/z=443.1 [M+H]⁺.

EXAMPLE 10aN-(1,3-benzoxazol-4-ylmethyl)-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 9 from5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 4-(bromomethyl)-1,3-benzoxazole.

¹H NMR (CDCl₃ 400 MHz): δ 8.23 (dd, J=2.0, 7.6 Hz, 1H), 8.18-8.16 (m,2H), 7.58 (dd, J=2.0, 7.6 Hz, 1H), 7.44-7.40 (m, 2H), 7.25 (s, 1H), 7.02(dd, J=5.2, 7.6 Hz, 1H), 6.18 (brs, 1H), 5.12-5.06 (m, 1H), 4.92 (d,J=5.6 Hz, 2H), 4.44 (q, dd, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.64 (d, J=6.4Hz, 6H), 1.38 (t, dd, J=7.2 Hz, 3H). LC-MS: t_(R)=1.97 minutes (MethodA), m/z=433 [M+H]⁺.

EXAMPLE 11a5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-1,3-benzoxazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 9 from5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 4-(chloromethyl)-2-methylbenzo[d]oxazole.

¹H NMR (CDCl₃ 400 MHz): δ 8.31-8.29 (m, 3H), 8.18 (dd, =2.0, 5.2 Hz,1H), 7.24 (s, 1H), 7.02 (dd, J=4.8, 7.2 Hz, 1H), 6.95 (s, 1H), 5.20-5.17(m, 1H), 4.62 (d, J=7.0 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 4.06 (s, 3H),3.85 (s, 3H), 3.33-3.26 (m, 1H), 1.47 (d, J=6.8 Hz, 6H), 1.30 (t, J=7.2Hz, 3H). LC-MS: t_(R)=2.11 minutes (Method L), m/z=457 [M+H]⁺.

EXAMPLE 12a5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-1,3-benzoxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 9 from5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-(chloromethyl)-2-methylbenzo[d]oxazole.

¹H NMR (CDCl₃ 400 MHz): δ8.24 (dd, J=2.0, 7.2 Hz, 1H), 8.15 (dd, 1 =2.0,4.8 Hz, 1H), 7.72 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.37 (dd, J=1.2, 8.4Hz, 1H), 7.21 (s, 1H), 7.01 (dd, J=4.8, 7.2 Hz, 1H), 4.85-4.79 (m, 1H),4.78 (brs, 1H), 4.64 (d, I =5.2 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 2.66(s, 3H), 2.65 (s, 3H), 1.61 (d, J=6.4 Hz, 6H), 1.31 (t, J=7.2 Hz, 3H).LC-MS: t_(R)=1.95 minutes (Method L), m/z=457.1 [M+H]⁺.

EXAMPLE 13aN-(1,3-benzoxazol-4-ylmethyl)-5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

To a solution of5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(80 mg, 0.18 mmol) in NMP (2 mL) was added4-(bromomethyl)benzo[d]oxazole (59 mg, 0.28 mmol), t-BuOK (42 mg, 0.37mmol) and NaI (55 mg, 0.37 mmol), the resulting mixture was degassed andpurged 3 times with N₂, then the mixture was stirred at 120° C. for 12hours. The mixture was cooled to 20° C. and filtered, and the filtercake was washed with ethyl acetate (20 mL×2). The filtrate wasconcentrated. Ethyl acetate (10 mL) and H₂O (10 mL) were added, theorganic layer was washed with H₂O (20 mL×3), brine (20 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashsilica gel chromatography (ethyl acetate/petroleum ether gradient 0˜50%)to affordN-(benzo[d]oxazol-4-ylmethyl)-5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.A solution ofN-(benzo[d]oxazol-4-ylmethyl)-5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(58 mg, 0.10 mmol) in TFA (2 mL) was stirred at 20° C. for 1 hour. Thesolution was dropwise added to TEA (30 ml) at 0° C. and stirred at 0° C.for 0.5 hour. The mixture was concentrated. The residue was diluted withethyl acetate (20 mL) and washed with water (20 mL×3), brine (20 mL),dried with anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by preparative HPLC to affordN-(1,3-benzoxazol-4-ylmethyl)-5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine.amine ¹H NMR (CDCl₃ 400 MHz): δ8.95 (d, J=4.8 Hz, 1H), 8.17 (s, 1H),8.13 (d, J=4.8 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.47-7.37 (m, 3H), 6.32(broad t, J=5.2 Hz, 1H), 5.14-5.06 (m, 1H), 4.94 (d, J=5.2 Hz, 2H), 4.70(q, J=6.8 Hz, 2H), 2.65 (s, 3H), 1.65 (d, J=6.4 Hz, 6H), 1.48 (t, J=6.8Hz, 3H) LC-MS: t_(R)=2.01 minutes (Method L), m/z=444 [M+H]⁺.

EXAMPLE 14a5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(2-methyl-1,3-benzoxazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 13 fromN-(benzo[d]oxazol-4-ylmethyl)-5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 4-(chloromethyl)-2-methylbenzo[d]oxazole. ¹H NMR (CDCl₃ 400 MHz):δ8.95 (d, J=4.8 Hz, 1H), 8.13 (d, J=4.8 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H),7.39 (s, 1H), 7.36-7.29 (m, 2H), 6.58 (brt, J=5.2 Hz, 1H), 5.23-5.14 (m,1H), 4.88 (d, J=5.2 Hz, 2H), 4.72 (q, J=7.2 Hz, 2H), 2.69 (s, 3H), 2.66(s, 3H), 1.66 (d, J=6.8 Hz, 6H), 1.51 (t, J=7.2 Hz, 3H). LC-MS:t_(R)=2.1 minutes (Method L), m/z=458 [M+H]⁺.

EXAMPLE 15aN-([1,2,4]triazolo[4,3-c]pyrimidin-5-ylmethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

A solution ofN-([1,2,4]triazolo[4,3-c]pyrimidin-5-ylmethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(crude from previous step directly) in trifluoroacetic acid (1.4 mL,0.019 mmol) was stirred at 50° C. for 1 hour. The reaction mixture wascooled to 20° C. and concentrated. The residue was diluted withsaturated NaHCO₃ aqueous solution (40 mL), then extracted with ethylacetate (20 mL×3). The combined organic layers were washed with brine(10 mL), dried over Na₂SO₄, and concentrated. The crude mixture waspurified by flash chromatography with petroleum ether/ethyl acetatefollowed by preparative HPLC to giveN-([1,2,4]triazolo[4,3-c]pyrimidin-5-ylmethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Acetonitrile-d₃, 400 MHz) δ9.22 (s, 1H), 8.15 (dd, J=2.0, 4.8Hz, 1H), 8.12 (dd, J=2.0, 7.2 Hz, 1H), 7.93 (d, J=6.8 Hz, 1H), 7.61 (d,J=6.8 Hz, 1H), 7.23 (s, 1H), 7.03 (dd, J=4.8, 7.2 Hz, 1H), 6.07 (br s,1H), 5.15-5.05 (m, 1H), 4.96 (d, J=4.8 Hz, 2H), 4.35 (q, J=7.2 Hz, 2H),2.51 (s, 3H), 1.60 (d, J=6.4 Hz, 6H), 1.23 (t, J=7.2 Hz, 3H). LC-MS(m/z) 444.2 (MH⁺); t_(R)=1.741 min (Method M).

EXAMPLE 16a5-(2-ethoxypyridin-3-yl)-N-(imidazo[1,2-c]pyrimidin-5-ylmethyl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 15 from5-(2-ethoxy-3-pyridyl)-N-(imidazo[1,2-c]pyrimidin-5-ylmethyl)-1-isopropyl-N-[(4-methoxyphenyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine.¹H NMR (Chloroform-d, 400 MHz): δ8.32 (d, J=6.8 Hz, 1H), 8.21 (d, J=3.6Hz, 1H), 8.21 (d, J=6.4 Hz, 1H),7.86 (s, 1H), 7.64-7.62 (m, 2H),7.27-7.26 (m, 1H), 7.08-7.05 (m, 1H), 6.54 (brs, 1H), 5.17-5.14 (m, 1H),4.80 (d, J=2.8 Hz, 2H), 4.53 (q, J=6.8 Hz, 2H), 2.68 (s, 3H), 1.74 (d,J=6.4 Hz, 6H), 1.48 (t, J=6.8 Hz, 3H). LC-MS (m/z) 443.3 (MH⁺);t_(R)=1.682 minutes (Method J).

EXAMPLE 1b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-(pyrimidin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

To a solution of5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine (500 mg, 1.5mmol) in NMP (1.5 mL) was added pyrimidin-2-ylmethanamine hydrochloride(437 mg, 3 mmol) and CsF (684 mg, 4.50 mmol), the resulting mixture washeated at 100° C. for 16 hours. The mixture was cooled to 25° C., thenethyl acetate(50 mL) and H₂O(30 mL) were added, the organic layer waswashed with H₂O (50 mL×3), brine (50 mL×2), then concentrated. Theresidue was purified by flash silica gel chromatography (ethylacetate/petroleum ether gradient 0100%) to afford5-bromo-1-isopropyl-3-methyl-N-(pyrimidin-2-ylmethyl)-1H-pyrazolo[4,3-b]pyridin-7-amine.To a solution of5-bromo-1-isopropyl-3-methyl-N-(pyrimidin-2-ylmethyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(100 mg, 0.28 mmol) in DMF (1 mL) was added3-ethoxy-4-(tributylstannyl)pyridazine (229 mg, 0.55 mmol), CuI (5 mg,0.028 mmol) and Pd(PPh₃)₄ (32 mg, 0.028 mmol), the reaction mixture wasdegassed with N₂ and heated at 100° C. for 16 hours. The mixture wascooled to 25° C. and filtered and the filter cake was washed with ethylacetate (10 mL). The filtrate was concentrated. The residue was purifiedby flash silica gel chromatography (MeOH/dichloromethane gradient 0˜5%)to give the crude. The crude was purified by preparative TLC (SiO₂,dichloromethane: MeOH=20:1) to afford the title compound. ¹H NMR (CDCl₃400 MHz): δ8.96 (d, J=4.8 Hz, 1H), 8.83 (d, J=5.2 Hz, 2H), 8.16 (d,J=4.8 Hz, 1H), 7.34-7.32 (m, 2H), 6.53 (brs, 1H), 5.16-5.10 (m, 1H),4.78-4.73 (m, 4H), 2.67 (s, 3H), 1.72 (d, J=6.8 Hz, 6H), 1.56 (t, J=7.2Hz, 3H). LC-MS: t_(R)=1.71 minutes (Method L), m/z=405 [M+H]⁺.

EXAMPLE 2b1-isopropyl-5-(3-methoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(1-methyl-1H-pyrazol-4-yl)methanamine andtributyl-(3-methoxypyridazin-4-yl)stannane.

¹H NMR (CDCl₃ 400 MHz): δ 8.98 (d, J=4.4 Hz, 1H), 8.09 (d, J=4.4 Hz,1H), 7.59 (s, 1H), 7.45 (s 1H), 7.23 (s, 1H), 4.79-4.73 (m, 1H), 4.65(brs, 1H), 4.42 (d, J=5.2 Hz, 2H), 4.22 (s, 3H), 3.94 (s, 3H), 2.64 (s,3H), 1.60 (d, J=6.4 Hz, 6H). LC-MS: t_(R)=1.6 minutes (Method C),m/z=393.1 [M+H]⁺.

EXAMPLE 3b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(1-methyl-1H-pyrazol-4-yl)methanamine andtributyl-(3-ethoxypyridazin-4-yl) stannane.

¹H NMR (CDCl₃, 400 MHz) δ 8.96 (d, J=4.4 Hz, 1H), 8.17 (d, J=4.4 Hz,1H), 7.58 (s, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 4.82-4.65 (m, 3H), 4.61(brs, 1H), 4.41 (d, J=4.4 Hz, 2H), 3.94 (s, 3H), 2.65 (s, 3H), 1.60 (d,J=6.8 Hz, 6H), 1.48 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.69 minutes (MethodC), m/z=407.1 [M+H]⁺.

EXAMPLE 4b1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(3-propoxypyridazin-4-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(1-methyl-1H-pyrazol-4-yl)methanamine and3-propoxy-4-(tributylstannyl)pyridazine.

¹H NMR (CDCl₃ 400 MHz): δ 8.98 (d, J=4.0 Hz, 1H), 8.16 (d, J=4.0 Hz,1H), 7.57 (s, 1H), 7.45 (s, 1H), 7.32 (s, 1H), 4.85-4.72 (m, 2H), 4.62(t, J=6.8 Hz, 2H), 4.42 (s, 2H), 3.94 (s, 3H), 2.65 (s, 3H), 1.93-1.88(m, 2H), 1.60 (d, J=6.8 Hz, 6H), 1.07 (t, J=7.6 Hz, 3H). LC-MS:t_(R)=1.8 minutes (Method L), m/z=421.1 [M+H]⁺.

EXAMPLE 5b5-(3-ethoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared in a way similar to example 1 from(+)-5,7-dibromo-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridine,(1-methyl-1H-pyrazol-4-yl)methanamine andtributyl-(3-ethoxypyridazin-4-yl) stannane.

¹H NMR (CDCl₃, 400 MHz) δ 8.96 (d, J=4.8 Hz, 1H), 8.18 (d, J=4.8 Hz,1H), 7.58 (s, 1H), 7.44 (s, 1H), 7.41 (s, 1H), 4.72 (q, J=7.2 Hz, 2H),4.52 (s, 1H), 4.47-4.43 (m, 1H), 4.41 (d, J=4.8 Hz, 2H), 3.94 (s, 3H),2.65 (s, 3H), 2.18-2.11 (m, 1H), 1.88-1.81 (m, 1H), 1.59 (d, J=6.4 Hz,3H), 1.48 (t, J=7.2 Hz, 3H), 0.83 (t, J=7.6 Hz, 3H). LC-MS: t_(R)=1.79minutes (Method L), m/z=421.1 [M+H]⁺.

EXAMPLE 6b5-(3-ethoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared in a way similar to example 1 from(+5,7-dibromo-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridine,(1-methyl-1H-pyrazol-4-yl)methanamine andtributyl-(3-ethoxypyridazin-4-yl) stannane.

¹H NMR (CDCl₃ 400 MHz): δ 8.96 (d, J=4.8 Hz, 1H), 8.18 (d, J=4.8 Hz,1H), 7.58 (s, 1H), 7.44 (s, 1H), 7.41 (s, 1H), 4.72 (q,J=7.2 Hz, 2H),4.54 (brs, 1H), 4.49-4.42 (m, 1H), 4.41 (d, J=4.8 Hz, 2H), 3.94 (s, 3H),2.65 (s, 3H), 2.21-2.07 (m, 1H), 1.90-1.79 (m, 1H), 1.59 (d, J=6.4 Hz,3H), 1.48 (t, J=7.2 Hz, 3H), 0.83 (t, J=7.6 Hz, 3H). LC-MS: t_(R)=1.79minutes (Method L), m/z=421.1 [M+H]⁺.

EXAMPLE 7b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-methoxy-3-pyridyl)methanamine and tributyl-(3-ethoxypyridazin-4-yl)stannane.

¹H NMR (CDCl₃ 400 MHz): δ 8.94 (d, J=4.8 Hz, 1H), 8.16-8.14 (m, 2H),7.59 (dd, J=2.0, 7.2 Hz 1H), 7.31 (s, 1H), 6.91 (dd, J=5.2, 7.2 Hz 1H),5.19 (brt, J=5.6 Hz, 1H), 4.90-4.87 (m, 1H), 4.66 (q, J=6.8 Hz, 2H),4.53 (d, J=5.6 Hz, 2H), 4.05 (s, 3H), 2.65 (s, 3H), 1.65 (d, J=6.4 Hz,6H), 1.40 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.95 minutes (Method L),m/z=434.1 [M+H]⁺.

EXAMPLE 8b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(5-methyl-1,3,4-oxadiazol-2-yl)methanamine andtributyl-(3-ethoxypyridazin-4-yl) stannane.

¹H NMR (CDCl₃ 400 MHz): δ 8.97 (d, J=4.8 Hz, 1H), 8.17 (d, J=4.8 Hz,1H), 7.38 (s, 1H), 5.39-5.33 (m, 1H), 4.97-4.92 (m, 1H), 4.77-4.73 (m,4H), 2.66 (s, 3H), 2.59 (s, 3H), 1.67 (d, J=6.4 Hz, 6H), 1.53 (t, J=7.2Hz, 3H). LC-MS: t_(R)=1.74 minutes (Method B), m/z=409.01 [M+H]⁺.

EXAMPLE 9b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(1-methyl-1H-pyrazol-3-yl)methanamine andtributyl-(3-ethoxypyridazin-4-yl) stannane.

¹H NMR (CDCl₃ 400 MHz): δ=8.94 (d, J=4.8 Hz, 1H), 8.15 (d, J=4.8 Hz,1H), 7.38 (d, J=2.4 Hz, 1H), 7.35 (s, 1H), 6.26 (d, J=2.4 Hz, 1H), 5.36(brt, J=4.4 Hz, 1H), 4.95-4.88 (m, 1H), 4.73 (q, J=6.8 Hz, 2H), 4.52 (d,J=4.8 Hz, 2H), 3.93 (s, 3H), 2.65 (s, 3H), 1.64 (d, J=6.4 Hz, 6H), 1.51(t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.76 minutes (Method L), m/z=407.1[M+H]⁺.

EXAMPLE 10b5-(3-ethoxypyridazin-4-yl)-N-[(5-fluoropyrimidin-2-yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(5-fluoropyrimidin-2-yl)methanamine hydrochloride and3-ethoxy-4-(tributylsta nnyl)pyridazine.

¹H NMR (CDCl₃, 400 MHz) δ 8.89 (d, J=4.8 Hz, 1H), 8.63 (s, 2H), 8.10 (d,J=4.8 Hz, 1H), 7.20 (s, 1H), 6.24 (brs, 1H), 5.05-4.99 (m, 1H),4.70-4.67 (m, 4H), 2.59 (s, 3H), 1.64 (d, J=6.4 Hz, 6H), 1.49 (t, J=7.2Hz, 3H). LC-MS: t_(R)=2.13 minutes (Method B), m/z=423 [M+H]⁺.

EXAMPLE 11b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(4-methylpyrimidin-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 1 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(4-methylpyrimidin-2-yl)methanamine and3-ethoxy-4-(tributylstannyl)pyridazine.

¹H NMR (CDCl₃ 400 MHz): δ 8.96 (d, J=4.0 Hz, 1H), 8.66 (d, J=4.8 Hz,1H), 8.14 (d, J=4.0 Hz, 1H), 7.29(s, 1H), 7.18 (d, J=4.8 Hz, 1H), 6.67(brs, 1H), 5.21-5.15 (m, 1H), 4.75 (q, J=6.8 Hz, 2H), 4.68 (s, 2H), 2.67(s, 3H), 2.61 (s, 3H), 1.73 (d, J=6.4 Hz, 6H), 1.56 (t, J=6.8 Hz, 3H).LC-MS: t_(R)=1.86 minutes (Method L), m/z=419.1 [M+H]⁺.

EXAMPLE 12b5-(3-ethoxy-4-pyridyl)-N-[(6-fluoro-2-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine.

To a solution of5-(3-ethoxypyridin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(50 mg, 0.16 mmol) in dioxane (2 mL) was added 6-fluoropicolinaldehyde(40 mg, 0.32 mmol) and Ti(Oi-Pr)₄ (91 mg, 0.32 mmol), the reactionmixture was heated at 100° C. for 16 hours. The mixture was cooled to20° C. and directly used for the next step. The reaction mixture wascooled to 0° C., then EtOH (2 mL) was added, followed by NaBH₄ (30 mg,0.80 mmol). The mixture was stirred at 25° C. for 1 hour. Saturatedaqueous NH₄Cl solution (1 mL) was added and the mixture was filteredthrough celite, the filter cake was washed with ethyl acetate (20 mL)and the filtrate was concentrated. The residue was purified bypreparative HPLC to afford the title compound.

¹H NMR (CDCl₃ 400 MHz): δ 8.39-8.36 (m 2H), 7.88-7.82 (m 2H), 7.26-7.25(m, 1H), 7.10 (s, 1H), 6.94-6.91 (m, 1H), 6.11 (brs, 1H), 5.13-5.06 (m,1H), 4.60 (d, J=4.4 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 1.72(d, J=6.4 Hz, 6H), 1.41 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.68 minutes(Method M), m/z=421 [M+H]⁺.

EXAMPLE 13b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 12 from5-(3-ethoxypyridin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1H-pyrazole-3-carbaldehyde.

¹H NMR (CDCl₃ 400 MHz): δ 8.40 (s, 1H), 8.36 (d, J=4.8 Hz, 1H), 7.86 (d,J=4.8 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.19 (s, 1H), 6.36 (d, J=2.0 Hz,1H), 5.38 (brs, 1H), 4.95-4.89 (m, 1H), 4.57 (d, J=5.2 Hz, 2H), 4.20 (q,J=6.8 Hz, 2H), 2.66 (s, 3H), 1.64 (d, J=6.4 Hz, 6H), 1.43 (t, J=6.8 Hz,3H) LC-MS: t_(R)=1.64 minutes (Method C), m/z=392.1 [M+H]⁺.

EXAMPLE 14b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 12 from5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand picolinaldehyde.

¹H NMR (CDCl₃ 400 MHz): δ 8.94 (d, J=4.8 Hz, 1H), 8.65-8.63 (d, J=5.2Hz, 1H), 8.15 (d, J=4.8 Hz, 1H), 7.75-7.73 (m, 1H), 7.37-7.35 (m, 1H),7.30-7.29 (m, 1H), 7.26 (s, 1H), 6.65 (brs, 1H), 5.14-5.07 (m, 1H), 4.71(q, J=7.2 Hz, 2H), 4.61 (d, J=4.0 Hz, 2H), 2.65 (s, 3H), 1.69 (d, J=6.4Hz, 6H), 1.51 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.75 minutes (Method L),m/z=404 [M+H]⁺.

EXAMPLE 15b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 12 from5-(3-ethoxypyridin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand picolinaldehyde.

¹H NMR (CDCl₃ 400 MHz): δ 8.64 (d, J=4.8 Hz, 1H), 8.40 (s, 1H), 8.37 (d,J=4.8 Hz, 1H), 7.87 (d, J=4.8 Hz, 1H), 7.76-7.72 (m, 1H), 7.35 (d, J=7.6Hz, 1H), 7.29 (d, J=4.8 Hz, 1H), 7.12 (s, 1H), 6.60 (brt, J=4.0 Hz, 1H),5.17-5.07 (m, 1H), 4.60 (d, J=4.0 Hz, 2H), 4.19 (q, J=6.8 Hz, 2H), 2.67(s, 3H), 1.70 (d, J=6.4 Hz, 6H), 1.43 (t, J=6.8 Hz, 3H). LC-MS:t_(R)=1.71 minutes (Method L), m/z=403.1 [M+H]⁺.

EXAMPLE 16b5-(3-ethoxypyridazin-4-yl)-N-[(2-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 12 from5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-fluoronicotinaldehyde.

¹H NMR (CDCl₃ 400 MHz): δ 8.94 (d, J=4.8 Hz, 1H), 8.21-8.20 (m, 1H),8.16 (d, J=4.8 Hz, 1H), 7.84-7.79 (m, 1H), 7.28 (s, 1H), 7.23-7.20 (m,1H), 5.04 (brs, 1H), 4.89-4.86 (m, 1H), 4.68 (d, J=5.6 Hz, 2H), 4.63 (q,J=7.2 Hz, 2H), 2.65 (s, 3H), 1.66 (d, J=6.4 Hz, 6H), 1.35 (t, J=7.2 Hz,3H). LC-MS: t_(R)=1.79 minutes (Method L), m/z=422 [M+H]⁺.

EXAMPLE 17b5-(3-ethoxy-4-pyridyl)-N-[(2-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 12 from5-(3-ethoxypyridin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-fluoronicotinaldehyde.

¹H NMR (CDCl₃ 400 MHz): δ 8.35-8.33 (m, 2H), 8.18 (d, J=4.8 Hz, 1H),7.85 (d, J=4.8 Hz, 1H), 7.82-7.80 (m, 1H), 7.23-7.19 (m, 1H), 7.11 (s,1H), 5.01 (brs, 1H), 4.92-4.83 (m, 1H), 4.65 (d, J=5.6 Hz, 2H), 4.11 (q,J=6.8 Hz, 2H), 2.66 (s, 3H), 1.66 (d, J=6.4 Hz, 6H), 1.29 (t, J=6.8 Hz,3H). LC-MS: t_(R)=1.51 minutes (Method M), m/z=421.1 [M+H]⁺.

EXAMPLE 18b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 12 from5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-methyl-1H-1,2,4-triazole-3-carbaldehyde. ¹H NMR (CDCl₃ 400 MHz): δ8.95 (d, J=4.8 Hz, 1H), 8.15 (d, J=4.8 Hz, 1H), 8.06 (s, 1H), 7.36 (s,1H), 5.61 (brs, 1H), 5.01-4.94 (m, 1H), 4.74 (q, J=7.2 Hz, 2H), 4.60 (d,J=4.8 Hz, 2H), 3.96 (s, 3H), 2.65 (s, 3H), 1.67 (d, J=6.8 Hz, 6H), 1.55(t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.61 minutes (Method L), m/z=408.1[M+H]⁺.

EXAMPLE 19b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 12 from5-(3-ethoxypyridin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-methyl-1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (CDCl₃ 400 MHz): δ 8.40 (s, 1H), 8.36 (d, J=4.4 Hz, 1H), 8.05 (s,1H), 7.87 (d, J=4.4 Hz, 1H), 7.19 (s, 1H), 5.55 (brs, 1H), 5.00-4.95 (m,1H), 4.57 (d, J=4.4 Hz, 2H), 4.22 (q, J=6.8 Hz, 2H), 3.95 (s, 3H), 2.66(s, 3H), 1.66 (d, J=6.8 Hz, 6H), 1.46 (t, J=6.8 Hz, 3H). LC-MS:t_(R)=1.56 minutes (Method L), m/z=407.1 [M+H]⁺.

EXAMPLE 20b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 12 from5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-methylthiazole-5-carbaldehyde.

¹H NMR (CDCl₃ 400 MHz): δ 8.96 (d, J=4.4 Hz, 1H), 8.16 (d, J=4.4 Hz,1H), 7.63 (s, 1H), 7.40 (s, 1H), 4.83-4.69 (m, 6H), 2.72 (s, 3H), 2.65(s, 3H), 1.62 (d, J=6.4 Hz, 6H), 1.47 (t, J=6.8 Hz, 3H).

LC-MS: t_(R)=1.76 minutes (Method L), m/z=424 [M+H]⁺.

EXAMPLE 21b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 12 from5-(3-ethoxypyridin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-methylthiazole-5-carbaldehyde.

1H NMR (CDCl₃ 400 MHz): δ=8.39 (s, 1H), 8.37 (d, J=4.8 Hz, 1H), 7.86 (d,J=4.8 Hz, 1H), 7.62 (s, 1H), 7.23 (s, 1H), 4.83-4.77 (m, 1H), 4.75-4.68(m, 3H), 4.20 (q, J=6.8 Hz, 2H), 2.72 (s, 3H), 2.66 (s, 3H), 1.62 (d,J=6.4 Hz, 6H), 1.40 (t, J=6.8 Hz, 3H). LC-MS: t_(R)=1.45 minutes (MethodM), m/z=423 [M+H]⁺.

EXAMPLE 22b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 12 from5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-methyl-1H-pyrazole-3-carbaldehyde.

¹H NMR (CDCl₃ 400 MHz): δ 8.95 (d, J=4.8 Hz, 1H), 8.15 (d, J=4.8 Hz,1H), 7.34 (s, 1H), 6.09 (s, 1H), 5.40 (brs, 1H), 4.94-4.87 (m, 1H), 4.73(q, J=6.8 Hz , 2H), 4.51 (d, J=4.4 Hz, 2H), 2.65 (s, 3H), 2.36 (s, 3H),1.64 (d, J=6.4 Hz, 6H), 1.51 (t, J=6.8 Hz, 3H). LC-MS: t_(R)=1.77minutes (Method L), m/z=407.1 [M+H]⁺.

EXAMPLE 23b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 12 from5-(3-ethoxypyridin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-methyl-1H-pyrazole-3-carbaldehyde.

¹H NMR (CDCl₃ 400 MHz): δ 8.40 (s, 1H), 8.37 (d, J=4.8 Hz, 1H), 7.87 (d,J=4.8 Hz, 1H), 7.17 (s, 1H), 6.07 (s, 1H), 5.37 (brs, 1H), 4.95-4.87 (m,1H), 4.49 (d, J=4.4 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 2.66 (s, 3H), 2.35(s, 3H), 1.64 (d, J=6.4 Hz, 6H), 1.43 (t, J=7.2 Hz, 3H). LC-MS:t_(R)=1.7 minutes (Method L), m/z=406.1 [M+H]⁺.

EXAMPLE 24b5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 12 from5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-methoxypicolinaldehyde.

¹H NMR (CDCl₃ 400 MHz): δ 8.96 (d, J=4.8 Hz, 1H), 8.17 (d, J=4.4 Hz,1H), 7.64 (dd, J=7.6, 8.4 Hz, 1H), 7.33 (s, 1H), 6.96 (dd, J=7.2, 0.8Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.25 (brt, J=4.0 Hz, 1H), 5.13-5.06 (m,1H), 4.74 (q, J=7.2 Hz, 2H), 4.57 (d, J=4.0 Hz, 2H), 4.02 (s, 3H), 2.67(s, 3H), 1.66 (d, J=6.4 Hz, 6H), 1.53 (t, J=6.8 Hz, 3H). LC-MS:t_(R)=2.1 minutes (Method L), m/z=434 [M+H]⁺.

EXAMPLE 25b5-(3-ethoxy-4-pyridyl)-1-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 12 from5-(3-ethoxypyridin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-methoxypicolinaldehyde.

¹H NMR (CDCl₃ 400 MHz): δ 8.40-8.37 (m, 2H), 7.88 (d, J=4.4 Hz, 1H),7.65-7.61 (m, 1H), 7.16 (s, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.74 (d, J=8.4Hz, 1H), 6.20 (brs, 1H), 5.13-5.06 (m, 1H), 4.54 (d, J=4.4 Hz, 2H), 4.21(q, J=6.8 Hz, 2H), 4.01 (s, 3H), 2.67 (s, 3H), 1.66 (d, J=6.4 Hz, 6H),1.44 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=1.81 minutes (Method M), m/z=433.1[M+H]⁺.

EXAMPLE 26b5-(3-ethoxypyridazin-4-yl)-N-[(6-fluoro-2-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 12 from5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-fluoropicolinaldehyde.

¹H NMR (CDCl₃ 400 MHz): δ 8.96 (d, J=4.8 Hz, 1H), 8.15 (d, J=4.4 Hz,1H), 7.89-7.83 (m, 1H), 7.29-7.28 (m, 2H), 6.95-6.92 (m, 1H), 6.18 (brs,1H), 5.11-5.08 (m, 1H), 4.72 (q, J=6.8 Hz, 2H), 4.62 (d, J=4.4 Hz, 2H),2.66 (s, 3H), 1.72 (d, J=6.4 Hz, 6H), 1.50 (t, J=6.8 Hz, 3H). LC-MS:t_(R)=1.95 minutes (Method L), m/z=422 [M+H]⁺.

EXAMPLE 27b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

A mixture of 5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine(0.3 g, 0.9 mmol), (1-methyl-1H-pyrazol-3-yl)methanamine (120 mg, 1.08mmol) and CsF (274 mg, 1.80 mmol) in NMP (8 mL) was stirred at 100° C.for 12 hours. The mixture was poured into water (20 mL), the aqueousphase was extracted with ethyl acetate (10 mL×3).The combined organicphase was washed with brine (10 mL×1), dried with anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by silica gelchromatography (silica gel, petroleum ether/ethyl acetate=1/0, 1/1) toafford5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine.A mixture of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(30 mg, 0.083 mmol), (3-ethoxypyridin-4-yl)boronic acid (28 mg, 0.17mmol), Pd(dppf)Cl₂ (6 mg, 0.008 mmol), K₂CO₃ (23 mg, 0.17 mmol) anddioxane (1.5 mL) in H₂O (1.5 mL) was stirred at 100° C. for 2 hours. Themixture was concentrated. The residue was purified by columnchromatography (SiO₂, petroleum ether/ethyl acetate=1/0 to 0:1) andpreparative HPLC to afford the title compound.

¹H NMR (CD₃CN 400 MHz): δ=8.39 (s, 1H), 8.26 (d, J=4.8 Hz, 1H), 7.74 (d,J=4.8 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.19 (s, 1H), 6.20 (d, J=2.4 Hz,1H), 5.71 (brt, J=5.2 Hz, 1H), 5.04-4.94 (m, 1H), 4.50 (d, J=5.2 Hz,2H), 4.19 (q, J=7.2 Hz, 2H), 3.80 (s, 3H), 2.50 (s, 3H), 1.54 (d, J=6.8Hz, 6H), 1.35 (t, J=6.8 Hz, 3H). LC-MS: t_(R)=1.71 minutes (Method L),m/z=406.1 [M+H]⁺.

EXAMPLE 28b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 27 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(1-methyl-1H-pyrazol-4-yl)methanamine and (3-ethoxypyridin-4-yl)boronicacid.

¹H NMR (CDCl₃ 400 MHz): δ 8.39-8.37 (m, 2H), 7.89-7.88 (m, 1H), 7.57 (s,1H), 7.44 (s, 1H), 7.22 (s, 1H), 4.80-4.73 (m, 1H), 4.59 (brs, 1H), 4.38(d, J=4.8 Hz, 2H), 4.20 (q, J=6.8 Hz, 2H), 3.93 (s, 3H), 2.66 (s, 3H),1.60 (d, J=6.8 Hz, 6H), 1.41 (t, J=6.8 Hz, 3H). LC-MS: t_(R)=1.66minutes (Method C), m/z=406.1 [M+H]⁺.

EXAMPLE 29b1-isopropyl-5-(3-methoxy-4-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 27 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(1-methyl-1H-pyrazol-4-yl)methanamine and (3-methoxy-4-pyridyl)boronicacid.

¹H NMR (CDCl₃ 400 MHz): δ 8.40 (s, 1H), 8.37 (d, J=4.8 Hz, 1H), 7.77 (d,J=5.2 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 7.04 (s, 1H), 4.80-4.73 (m,1H), 4.63-4.61 (m, 1H), 4.38 (d, J=4.8 Hz, 2H), 3.93 (s, 6H), 2.65 (s,3H), 1.59 (d, J=6.8 Hz, 6H). LC-MS: t_(R)=1.57 minutes (Method C),m/z=392 [M+H]⁺.

EXAMPLE 30b5-(3-ethoxy-4-pyridyl)-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 27 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-methoxy-3-pyridyl)methanamine and (3-ethoxypyridin-4-yl)boronic acid.

¹H NMR (CDCl₃ 400 MHz): δ 8.36-8.33 (m, 2H), 8.14 (dd, J=1.6, 4.8 Hz,1H), 7.84 (d, J=4.8 Hz, 1H), 7.59 (dd, J=1.6, 7.2 Hz, 1H), 7.14 (s, 1H),6.89 (dd, J=5.2, 7.2 Hz, 1H), 5.15 (brt, J=6.0 Hz, 1H), 4.91-4.84 (m,1H), 4.49 (d, J=6.0 Hz, 2H), 4.12 (q, J=6.8 Hz, 2H), 4.03 (s, 3H), 2.65(s, 3H), 1.64 (d, J=6.4 Hz, 6H), 1.32 (t, J=6.8 Hz, 3H). LC-MS:t_(R)=1.64 minutes (Method A), m/z=433.1 [M+H]⁺.

EXAMPLE 31b1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(3-propoxy-4-pyridyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 27 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(1-methyl-1H-pyrazol-4-yl)methanamine and (3-propoxypyridin-4-yl)boronicacid.

¹H NMR (CDCl₃, 400 MHz) δ 8.39 (s, 1H), 8.36 (d, J=4.8 Hz, 1H), 7.85 (d,J=4.8 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 7.18 (s, 1H), 4.81-4.69 (m,1H), 4.52 (brs, 1H), 4.37 (d, J=4.8 Hz, 2H), 4.09 (t, J=6.4 Hz, 2H),3.94 (s, 3H), 2.65 (s, 3H), 1.87-1.72 (m, 2H), 1.60 (d, J=6.8 Hz, 6H),1.03 (t, J=7.2 Hz, 3H). LC-MS: t_(R)=2.03 minutes (Method B), m/z=420.1[M+H]⁺.

EXAMPLE 32b5-(3-ethoxy-4-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared in a way similar to example 27 from(+)-5,7-dibromo-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridine,(1-methyl-1H-pyrazol-4-yl)methanamine and (3-ethoxypyridin-4-yl)boronicacid.

¹H NMR (CDCl₃, 400 MHz) δ 8.47-8.32 (m, 2H), 7.89 (d, J=4.8 Hz, 1H),7.57 (s, 1H), 7.43 (s, 1H), 7.23 (s, 1H), 4.52-4.41 (m, 2H), 4.38 (d,J=4.8 Hz, 2H), 4.20 (q, J=6.8 Hz, 2H), 3.93 (s, 3H), 2.66 (s, 3H),2.22-2.09 (m, 1H), 1.92-1.78 (m, 1H), 1.59 (d, J=6.4 Hz, 3H), 1.42 (t,J=6.8 Hz, 3H), 0.84 (t, J=7.6 Hz, 3H). LC-MS: t_(R)=1.75 minutes (MethodL), m/z=420.1 [M+H]⁺.

EXAMPLE 34b5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 27 from5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(5-methyl-1,3,4-oxadiazol-2-yl)methanamine and(3-ethoxypyridin-4-yl)boronic acid.

¹H NMR (CDCl₃ 400 MHz): δ 8.41 (s, 1H), 8.37 (d, J=5.2 Hz, 1H), 7.88 (d,J=4.8 Hz, 1H), 7.21 (s, 1H), 5.29 (br s, 1H), 4.97-4.90 (m, 1H), 4.71(d, J=5.2 Hz, 2H), 4.23 (q, J=6.8 Hz, 2H), 2.66 (s, 3H), 2.58 (s, 3H),1.67 (d, J=6.8 Hz, 6H), 1.45 (t, J=6.8 Hz, 3H). LC-MS: t_(R)=1.59minutes (Method L), m/z=408.1 [M+H]⁺.

EXAMPLE 35b1-isopropyl-3-methyl-5-(2-methyl-1,3-benzoxazol-4-yl)-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

To a solution of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(50 mg, 0.14 mmol) in dioxane (2 mL) was added4-bromo-2-methylbenzo[d]oxazole (58 mg, 0.28 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (70 mg, 0.28mmol), Cs₂CO₃ (90 mg, 0.28 mmol) and Pd(dppf)Cl₂ (20 mg, 0.03 mmol). Themixture was bubbled with N₂ and heated at 100° C. for 16 hours. Themixture was concentrated. The residue was purified by preparative TLC(SiO₂, dichloromethane/MeOH=20/1) to give the crude product. The crudeproduct was purified by preparative HPLC to give1-isopropyl-3-methyl-5-(2-methyl-1,3-benzoxazol-4-yl)-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine.¹H NMR (CDCl₃ 400 MHz): δ 8.24 (dd, J=1.2, 8.0 Hz, 1H), 7.89 (s, 1H),7.63 (s, 1H), 7.60 (s, 1H), 7.50 (dd, J=1.2, 8.0 Hz, 1H), 7.43 (dd,J=8.0, 8.0 Hz, 1H), 4.80-4.71 (m, 1H), 4.56 (brs, 1H), 4.48 (d, J=5.2Hz, 2H), 3.92 (s, 3H), 2.68 (s, 3H), 2.67 (s, 3H), 1.58 (d, J=6.8 Hz,6H). LC-MS: t_(R)=1.71 minutes (Method A), m/z=416 [M+H]⁺.

EXAMPLE 36b1-isopropyl-3-methyl-5-(2-methyl-1,3-benzoxazol-7-yl)-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 35 from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 7-bromo-2-methylbenzo[d]oxazole .

¹H NMR (CDCl₃ 400 MHz): δ 8.13 (dd, J=1.2, 8.0 Hz, 1H), 7.68 (dd, J=1.2,8.0 Hz, 1H), 7.62 (s, 1H), 7.47 (s, 1H), 7.44 (dd, J=8.0, 8.0 Hz, 1H),7.30 (s, 1H), 4.80-4.75 (m, 1H), 4.66 (brs, 1H), 4.48 (d, J=4.8 Hz, 2H),3.94 (s, 3H), 2.70 (s, 3H), 2.69 (s, 3H), 1.61 (d, J=6.8 Hz, 6H). LC-MS:t_(R)=1.58 minutes (Method A), m/z=416 [M+H]⁺.

EXAMPLE 37b5-(1,3-benzoxazol-7-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 35 from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 7-bromobenzo[d]oxazole. ¹H NMR (CDCl₃ 400 MHz): δ 8.27 (d, J=8.0 Hz,1H), 8.20 (s, 1H), 7.82 (d, J=6.8 Hz, 1H), 7.61 (s, 1H), 7.52 (dd,J=8.0, 6.8 Hz, 1H), 7.47 (s, 1H), 7.34 (s, 1H), 4.80-4.74 (m, 1H), 4.64(brs, 1H), 4.48 (d, J=4.8 Hz, 2H), 3.94 (s, 3H), 2.69 (s, 3H), 1.61 (d,J=6.8 Hz, 6H). LC-MS: t_(R)=1.71 minutes (Method C), m/z=402 [M+H]⁺.

EXAMPLE 38b5-(1H-indol-7-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

To a mixture of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(100 mg, 0.28 mmol) in dioxane (2 mL) and H₂O (1 mL) was added7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (100 mg, 0.41mmol), Cs₂CO₃ (179 mg, 0.55 mmol) and Pd(dppf)Cl₂ (20 mg, 0.03 mmol).The mixture was bubbled with N₂ and heated at 100° C. for 16 hours. Themixture was cooled to 25° C. and extracted with ethyl acetate (20 mL×2).The combined organic layers were washed with H₂O (20 mL), brine (20 mL),and dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The residue was purified by flash silica gel chromatography(ethyl acetate/petroleum ether, gradient 10˜100%) to give5-(1H-indol-7-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine.¹H NMR (CDCl₃ 400 MHz): δ 11.58 (brs, 1H), 7.74-7.71 (m, 2H), 7.61 (s,1H), 7.46-7.42 (m, 2H), 7.22-7.18 (m, 2H), 6.62 (s, 1H), 4.79-4.72 (m,1H), 4.56 (brs, 1H), 4.47 (d, J=4.4 Hz, 2H), 3.94 (s, 3H), 2.72 (s, 3H),1.61 (d, J=6.4 Hz, 6H). LC-MS: t_(R)=1.66 minutes (Method A), m/z=400[M+H]⁺.

EXAMPLE 39b5-(1H-indazol-7-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared in a way similar to example 38 from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 1H-indazol-7-ylboronic acid. ¹H NMR (CDCl₃ 400 MHz): δ 12.76 (brs,1H), 8.14 (s, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.81 (d, J=7.2 Hz, 1H), 7.61(s, 1H), 7.46 (s, 1H), 7.27-7.23 (m, 1H), 7.16 (s, 1H), 4.81-4.71 (m,1H), 4.62 (brs, 1H), 4.48 (d, J=4.8 Hz, 2H), 3.94 (s, 3H), 2.72 (s, 3H),1.61 (d, J=6.4 Hz, 6H). LC-MS: t_(R)=1.74 minutes (Method C), m/z=401.1[M+H]⁺.

SUPPORTING EXAMPLES SUPPORTING EXAMPLE S15-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

To a solution of5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine (100 mg,0.41 mmol) in NMP (2 mL) was added CsF (187 mg, 1.23 mmol, 45 μL) and(5-methyl-1,3,4-oxadiazol-2-yl)methanamine hydrochloride (74 mg, 0.49mmol). The mixture was stirred at 100° C. for 18 hours. Water (30 mL)was added and the mixture was extracted with ethyl acetate (30 mL×3).The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄ and concentrated. The crude mixture was purified by preparativeHPLC to give5-chloro-1-isopropyl-3-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(50 mg).

To a solution of5-chloro-1-isopropyl-3-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(50 mg, 70 μmop and (2-ethoxypyridin-3-yl)boronic acid (21 mg, 0.13mmol) in dioxane (2 mL) and H₂O (0.7 mL) was added Cs₂CO₃ (57 mg, 175μmol) and Pd(1,1′-bis(diphenylphosphino)ferrocene)Cl₂ (10 mg, 14 umol).The mixture was purged with nitrogen for 3 minutes then stirred at 100°C. for 30 minutes under microwave irradiation. Water (30 mL) was addedand the mixture was extracted with ethyl acetate (30 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over Na₂SO₄ andconcentrated. The crude mixture was purified by preparative TLC withdichloromethane:methanol=20:1 twice, and then the crude product wasfurther purified by preparative HPLC to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(6.1 mg).

¹H NMR (chloroform-d, 400 MHz) δ 8.28-8.26 (m, 1H), 8.19-8.18 (m, 1H),7.23 (s, 1H), 7.05-7.02 (m, 1H), 5.27 (brs, 1H), 4.96-4.90 (m, 1H), 4.71(d, J=1.2 Hz, 2H), 4.53-4.48 (m, 2H), 2.65 (s, 3H), 2.57 (s, 3H), 1.66(d, J=6.4 Hz, 6H), 1.43 (t, J=6.8 Hz, 3H). LC-MS (m/z) 408.2 (MH⁺);t_(R)=2.08 minutes (Method B).

The following examples were prepared in a similar manner:

SUPPORTING EXAMPLE S25-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methylthiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (5-methylthiazol-2-yl)methanamine dihydrochloride and5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 500 MHz) δ 8.21-8.14 (m, 2H), 7.42 (d, J=1.4 Hz, 1H),7.21 (t, J=5.6 Hz, 1H), 7.11-7.05 (m, 2H), 5.23 (hept, J=6.4 Hz, 1H),4.75 (d, J=5.5 Hz, 2H), 4.31 (q, J=7.0 Hz, 2H), 2.48 (s, 3H), 2.35 (s,3H), 1.50 (d, J=6.4 Hz, 6H), 1.24 (t, J=7.1 Hz, 3H). LC-MS (m/z) 423(MH⁺); t_(R)=0.61 minutes (Method D).

SUPPORTING EXAMPLE S35-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methylisoxazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (5-methylisoxazol-3-yl)methanamine and5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 500 MHz) δ 8.28 (d, J=7.3 Hz, 1H), 8.29-8.17 (m,1H), 7.29 (s, 1H), 7.04 (m, 1H), 6.07 (s, 1H), 5.19 (brs, 1H), 4.90(hept, J=6.4 Hz, 1H), 4.59 (d, J=5.2 Hz, 2H), 4.50 (q, J=7.0 Hz, 2H),2.67 (s, 3H), 2.47 (s, 3H), 1.66 (d, J=6.1, 6H), 1.43 (q, J=7.1 Hz, 3H).LC-MS (m/z) 407.3 (MH⁺); t_(R)=0.54 minutes (Method E).

SUPPORTING EXAMPLE S45-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyloxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (2-methyloxazol-5-yl)methanamine and5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.21-8.15 (m, 2H), 7.14 (s, 1H), 7.09 (dd,J=7.3, 4.8 Hz, 1H), 6.90 (s, 1H), 6.82 (t, J=5.7 Hz, 1H), 5.16 (hept,J=6.4 Hz, 1H), 4.55 (d, J=5.5 Hz, 2H), 4.39 (q, J=7.0 Hz, 2H), 2.47 (s,3H), 2.37 (s, 3H), 1.45 (d, J=6.4 Hz, 6H), 1.26 (t, J=7.0 Hz, 3H). LC-MS(m/z) 407.1 (MH⁺); t_(R)=0.53 minutes (Method D).

SUPPORTING EXAMPLE S55-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyltriazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (2-methyl-2H-1,2,3-triazol-4-yl)methanamine and5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.21-8.15 (m, 2H), 7.64 (s, 1H), 7.10-7.08(m, 2H), 6.88 (t, J=5.6 Hz, 1H), 5.19 (hept, J=6.3 Hz, 1H), 4.59 (d,J=5.1 Hz, 2H), 4.34 (q, J=7.0 Hz, 2H), 4.11 (s, 3H), 2.48 (s, 3H), 1.48(d, J=5.7 Hz, 6H), 1.28-1.20 (t, J=7.0 Hz, 3H). LC-MS (m/z) 407.1 (MH⁺);t_(R)=0.55 minutes (Method D).

SUPPORTING EXAMPLE S65-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methyltriazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-1,2,3-triazol-4-yl)methanamine and5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.21-8.14 (m, 2H), 7.90 (s, 1H), 7.13 (s,1H), 7.08 (dd, J=7.3, 4.9 Hz, 1H), 6.88 (t, J=5.7 Hz, 1H), 5.18 (hept,J=6.4 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 4.34 (q, J=7.0 Hz, 2H), 3.98 (s,3H), 2.47 (s, 3H), 1.47 (d, J=6.3 Hz, 6H), 1.25 (t, J=7.0 Hz, 3H). LC-MS(m/z) 407.3 (MH⁺); t_(R)=0.45 minutes (Method E).

SUPPORTING EXAMPLE S75-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1H-pyrazol-4-yl)methanamine hydrochloride and5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 600 MHz) δ 8.27 (dd, J=7.3, 2.0 Hz, 1H), 8.18 (dd,J=4.8, 1.9 Hz, 1H), 7.69 (s, 2H), 7.25 (s, 1H), 7.03 (dd, J=7.3, 4.9 Hz,1H), 4.76 (hept, J=6.4 Hz, 1H), 4.55 (brds, 1H), 4.46 (m, 4H), 2.63 (s,3H), 1.59 (d, J=6.5 Hz, 6H), 1.39 (t, J=7.0 Hz, 3H). LC-MS (m/z) 392.1(MH⁺); t_(R)=0.50 minutes (Method D).

SUPPORTING EXAMPLE S85-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (2-methyl-2H-tetrazol-5-yl)methanamine and5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27 (dd, J=7.2, 2.0 Hz, 1H), 8.18 (dd,J=5.2, 2.0 Hz, 1H), 7.26 (s, 1H), 7.04-7.01 (m, 1H), 5.33-5.31 (m, 1H),4.96-4.93 (m, 1H), 4.80 (d, J=5.2 Hz, 2H), 4.50 (q, J=6.8 Hz, 2H), 4.39(s, 3H), 2.65 (s, 3H), 1.67 (d, J=6.4 Hz, 6H), 1.44 (t, J=6.8 Hz, 3H).LC-MS (m/z) 408.1 (MH⁺); t_(R)=1.96 minutes (Method C).

SUPPORTING EXAMPLE S95-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine and5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d6, 400 MHz): δ 8.18-8.16 (m, 2H), 7.60 (s, 1H), 7.41 (s,1H), 7.10-7.06 (m, 2H), 6.68-6.65 (m, 1H), 5.19-5.12 (m, 1H), 4.39-4.34(m, 4H), 3.77 (s, 3H), 2.46 (s, 3H), 1.15 (d, J=6.4 Hz, 6H), 1.25 (t,J=7.2 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺); t_(R)=2.50 minutes (Method B).

SUPPORTING EXAMPLE S105-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(3-methylisoxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (3-methylisoxazol-5-yl)methanamine and5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.28-8.26 (m, 1H), 8.15-8.18 (m, 1H),7.20 (s, 1H), 7.04-7.00 (m, 1H), 6.10 (s, 1H), 4.87 (brs, 2H), 4.66-4.65(m, 2H), 4.45 (q, J=7.2 Hz, 2H), 2.64 (s, 3H), 2.29 (s, 3H), 1.63 (d,J=6.8 Hz, 6H), 1.36 (t, J=7.2 Hz, 3H). LC-MS (m/z) 407.1 (MH⁺);t_(R)=2.05 minutes (Method C).

SUPPORTING EXAMPLE S115-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (2-methylthiazol-4-yl)methanamine and5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.26 (dd, JJJ=7.6, 2.0 Hz, 1H), 8.17(dd, J=4.8, 2.0 Hz, 1H), 7.18 (s, 1H), 7.05-7.01 (m, 2H), 5.40-5.27 (m,1H), 4.96-4.90 (m, 1H), 4.59 (d, J=5.2 Hz, 2H), 4.46 (q, J=7.2 Hz, 2H),2.75 (s, 3H), 2.65 (s, 3H), 1.65 (d, J=6.4 Hz, 6H), 1.38 (t, J=7.2 Hz,3H). LC-MS (m/z) 423 (MH⁺); t_(R)=1.90 minutes (Method A).

SUPPORTING EXAMPLE S121-cyclopropyl-5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine and5,7-dibromo-1-cyclopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Cloroform-d, 400 MHz): (δ 8.26-8.23 (m, 1H), 8.19-8.17 (m, 1H),7.57 (s, 1H), 7.44 (s, 1H), 7.16 (s, 1H), 7.04-7.01 (m, 1H), 5.64 (brs,1H), 4.50-4.45 (m, 2H), 4.39 (d, J=4.4 Hz, 2H), 3.93 (s, 3H), 3.72-3.70(m, 1H), 2.61 (s, 3H), 1.46-1.38 (m, 5H), 1.16-1.11 (m, 2H). LC-MS (m/z)404.1 (MH⁺); t_(R)=1.88 minutes (Method C).

SUPPORTING EXAMPLE S135-(2-ethoxy-3-pyridyl)-N-[(1-methylpyrazol-4-yl)methyl]-1-propyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine dihydrochloride and5,7-dibromo-1-propyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.16-8.11 (m, 2H), 8.04 (s, 1H), 7.49(s, 1H), 7.37 (s, 1H), 7.17 (s, 1H), 6.97-6.94 (m, 1H), 4.42-4.32 (m,7H), 3.86 (s, 3H), 1.85 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H), 0.86(t, J=7.2 Hz, 3H). LC-MS (m/z) 392.2 (MH⁺); t_(R)=1.87 minutes (MethodC).

SUPPORTING EXAMPLE S145-(2-ethoxypyridin-3-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine and7-bromo-5-chloro-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Methanol-d₄, 600 MHz) δ 8.18-8.14 (m, 2H), 7.95 (dd, J=7.3, 2.0Hz, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.08-7.04 (m, 2H), 6.24-6.17 (m,1H), 5.24-5.18 (m, 2H), 5.15-5.08 (m, 2H), 4.45 (s, 2H), 4.38 (q, J=7.0Hz, 2H), 3.85 (s, 3H), 1.26 (t, J=7.0 Hz, 3H). LC-MS (m/z) 406.2 (MH⁺);t_(R)=0.41 minutes (Method D).

SUPPORTING EXAMPLE S155-(2-ethoxypyridin-3-yl)-1-methyl-N-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(racemic)

Prepared from 1-(1-methyl-1H-pyrazol-4-yl)ethan-1-amine and7-bromo-5-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 500 MHz) δ 8.24-8.17 (m, 2H), 8.09 (s, 1H), 7.54(s, 1H), 7.39 (s, 1H), 7.17 (s, 1H), 7.03 (dd, J=7.3, 5.1 Hz, 1H), 4.84(m, 1H), 4.73 (d, J=5.9 Hz, 1H), 4.54-4.37 (m, 2H), 4.35 (s, 3H), 3.91(s, 3H), 1.72 (d, J=7.0 Hz 3H), 1.36 (t, J=6.5 Hz, 3H). LC-MS (m/z)378.2 (MH⁺); t_(R)=0.44 minutes (Method D).

SUPPORTING EXAMPLE S165-(2-ethoxypyridin-3-yl)-1-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine and5,7-dibromo-1-methyl-1H-pyrazolo[4,3-b]pyridine

¹H NMR (Methanol-d₄, 400 MHz) δ 8.15-8.14 (m, 1H), 7.93-7.92 (m, 2H),7.60 (s, 1H), 7.50 (s, 1H), 7.038 (dd, J=4.8 Hz, J=6.8 Hz, 1H), 6.94 (s,1H), 4.46 (s, 2H), 4.40-4.34 (m, 6H), 3.83 (s, 3H), 1.25 (t, J=6.8 Hz,3H). LC-MS (m/z) 364.1 (MH⁺); t_(R)=1.71 minutes (Method C).

SUPPORTING EXAMPLE S175-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methylimidazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-imidazol-2-yl)methanamine and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.19 (dd, J=4.9, 2.0 Hz, 1H), 8.09-8.12 (m,2H), 7.35 (s, 1H), 7.13-7.05 (m, 2H), 6.83-6.76 (m, 2H), 5.25 (hept,J=6.5 Hz, 1H), 4.56 (d, J=4.9 Hz, 2H), 4.42 (q, J=7.0 Hz, 2H), 3.71 (s,3H), 1.51 (d, J=6.4 Hz, 6H), 1.38 (t, J=7.0 Hz, 3H). LC-MS (m/z) 392.1(MH⁺); t_(R)=0.35 minutes (Method D).

SUPPORTING EXAMPLE S185-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-5-yl)methanamine dihydrochloride and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.20-8.12 (m, 3H), 7.33 (d, J=1.8 Hz, 1H),7.14 (s, 1H), 7.08 (dd, J=7.4, 4.8 Hz, 1H), 6.89 (t, J=5.4 Hz, 1H), 6.19(d, J=1.8 Hz, 1H), 5.29 (hept, J=6.5 Hz, 1H), 4.59 (d, J=5.3 Hz, 2H),4.36 (q, J=7.0 Hz, 2H), 3.88 (s, 3H), 1.50 (d, J=6.3 Hz, 6H), 1.24 (t,J=7.0 Hz, 3H). LC-MS (m/z) 392.1 (MH⁺); t_(R)=0.49 minutes (Method D).

SUPPORTING EXAMPLE S195-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-3-yl)methanamine and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.19-8.13 (m, 2H), 8.09 (s, 1H), 7.59 (d,J=2.2 Hz, 1H), 7.14 (s, 1H), 7.07 (dd, J=7.4, 4.8 Hz, 1H), 6.85 (t,J=5.7 Hz, 1H), 6.17 (d, J=2.1 Hz, 1H), 5.27 (hept, J=6.4 Hz, 1H), 4.46(d, J=5.6 Hz, 2H), 4.36 (q, J=7.0 Hz, 2H), 3.78 (s, 3H), 1.50 (d, J=6.3Hz, 6H), 1.29 (t, J=7.0 Hz, 3H). LC-MS (m/z) 392.1 (MH⁺); t_(R)=0.54minutes (Method D).

SUPPORTING EXAMPLE S205-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(thiazol-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared from thiazol-2-ylmethanamine hydrochloride and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine

¹H NMR (DMSO-d₆, 600 MHz). δ 8.18-8.13 (m, 3H), 7.78 (d, J=3.3 Hz, 1H),7.62 (d, J=3.3 Hz, 1H), 7.32 (t, J=5.7 Hz, 1H), 7.12 (s, 1H), 7.06 (dd,J=6.9, 5.4 Hz, 1H), 5.32 (hept, J=6.5 Hz, 1H), 4.86 (d, J=5.6 Hz, 2H),4.29 (q, J=7.0 Hz, 2H), 1.54 (d, J=6.4 Hz, 6H), 1.21 (t, J=7.0 Hz, 3H).LC-MS (m/z) 395 (MH⁺); t_(R)=0.54 minutes (Method D).

SUPPORTING EXAMPLE S215-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methylimidazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-imidazol-4-yl)methanamine and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.19-8.13 (m, 2H), 8.09 (s, 1H), 7.52 (s,1H), 7.15 (s, 1H), 7.07 (dd, J=7.3, 4.9 Hz, 1H), 6.96 (s, 1H), 6.76 (t,J=5.5 Hz, 1H), 5.25 (hept, J=6.5 Hz, 1H), 4.40 (d, J=5.4 Hz, 2H), 4.35(q, J=7.0 Hz, 2H), 3.57 (s, 3H), 1.50 (d, J=6.3 Hz, 6H), 1.27 (t, J=7.0Hz, 3H). LC-MS (m/z) 392.1 (MH⁺); t_(R)=0.39 minutes (Method D).

SUPPORTING EXAMPLE S225-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(4-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared from pyridin-4-ylmethanamine and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Methanol-d₄, 600 MHz) δ 8.52-8.48 (m, 2H), 8.11 (dd, J=5.0, 1.9Hz, 1H), 8.06 (s, 1H), 7.90 (dd, J=7.4, 2.0 Hz, 1H), 7.51-7.47 (m, 2H),7.01 (dd, J=7.4, 4.9 Hz, 1H), 6.74 (s, 1H), 5.28 (hept, J=6.5 Hz, 1H),4.72 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 1.64 (d, J=6.4 Hz, 6H), 1.07 (t,J=7.0 Hz, 3H). LC-MS (m/z) 389.1 (MH⁺); t_(R)=0.38 minutes (Method D).

SUPPORTING EXAMPLE S235-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(m-tolylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared from m-tolylmethanamine hydrochloride and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.22-8.17 (m, 3H), 7.33-7.19 (m, 5H),7.03-7.00 (m, 1H), 4.89-4.86 (m, 2H), 4.53 (d, J=5.2 Hz, 2H), 4.42 (q,J=7.2 Hz, 2H), 2.39 (s, 3H), 1.65 (d, J=6.4 Hz, 6H), 1.33 (t, J=7.2 Hz,3H). LC-MS (m/z) 402.1 (MH⁺); t_(R)=2.57 minutes (Method F).

SUPPORTING EXAMPLE S245-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(p-tolylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared from p-tolylmethanamine and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.23-8.17 (m, 3H), 7.34-7.32 (m, 2H),7.24-7.22 (m, 3H), 7.03-7.00 (m, 1H), 4.89-4.74 (m, 2H), 4.52 (d, J=4.8Hz, 2H), 4.42 (q, J=6.8 Hz, 2H), 2.39 (s, 3H), 1.65 (d, J=6.8 Hz, 6H),1.35 (t, J=6.8 Hz, 3H). LC-MS (m/z) 402.1 (MH⁺); t_(R)=2.17 minutes(Method A).

SUPPORTING EXAMPLE S255-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine dihydrochloride and5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.22-8.16 (m, 3H), 7.57 (s, 1H), 7.44(s, 1H), 7.24 (s, 1H), 7.03-7.00 (m, 1H), 4.82-4.77 (m, 1H), 4.60 (brs,1H), 4.46 (q, J=7.2 Hz, 2H), 4.39 (d, J=4.8 Hz, 2H), 3.93 (s, 3H), 1.62(d, J=6.4 Hz, 6H), 1.39 (t, J=7.2 Hz, 3H). LC-MS (m/z) 392.2 (MH⁺);t_(R)=1.86 minutes (Method C).

SUPPORTING EXAMPLE S265-(2-ethoxy-3-pyridyl)-1-ethyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine and5,7-dibromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.22-8.11 (m, 3H), 7.56 (s, 1H), 7.43(s, 1H), 7.23 (s, 1H), 7.03-7.00 (m, 1H), 4.56-4.39 (m, 7H), 3.92 (s,3H), 1.51 (t, J=7.2 Hz, 3H), 1.38 (t, J=7.2 Hz, 3H). LC-MS (m/z) 378.2(MH⁺); t_(R)=1.79 minutes (Method G).

SUPPORTING EXAMPLE S275-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine and5,7-dibromo-3-methyl-1-(oxetan-3-yl)-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Cloroform-d, 400 MHz) δ 8.30-8.28 (m, 1H), 8.20-8.18 (m, 1H),7.54 (s, 1H), 7.43 (s, 1H), 7.32 (s, 1H), 7.05-7.02 (m, 1H), 5.85-5.75(m, 1H), 5.55 (brs, 1H), 5.18-5.11 (m, 4H), 4.51-4.45 (m, 2H), 4.41 (d,J=4.8 Hz, 2H), 3.92 (s, 3H), 2.64 (s, 3H), 1.40 (t, J=7.2 Hz, 3H). LC-MS(m/z) 420.1 (MH⁺); t_(R)=1.99 minutes (Method B).

SUPPORTING EXAMPLE S285-(2-ethoxy-3-pyridyl)-1,3-dimethyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from (1-methyl-1H-pyrazol-4-yl)methanamine and5,7-dichloro-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.28-8.26 (m, 1H), 8.19-8.18 (m, 1H),7.56 (s, 1H), 7.44 (s, 1H), 7.21 (s, 1H), 7.04-7.01 (m, 1H), 4.63 (brs,1H), 4.47 (q, J=6.8 Hz, 2H), 4.38 (d, J=4.8 Hz, 2H), 4.23 (s, 3H), 3.92(s, 3H), 2.62 (s, 3H), 1.39 (t, J=7.2 Hz, 3H). LC-MS (m/z) 378.2 (MH⁺);t_(R)=1.93 minutes (Method B).

SUPPORTING EXAMPLE S295-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((4-methylthiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

To a solution of5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(50 mg, 0.16 mmol) in THF (3 mL) was added Ti(i-PrO)₄ (91 mg, 0.32 mmol,95 μL) and 4-methylthiazole-2-carbaldehyde (41 mg, 0.32 mmol, 35 μL).The mixture was stirred at 50° C. for 18 hours. The reaction mixture wascooled to 0° C., then NaBH₄ (30 mg, 0.80 mmol) was added into themixture slowly and the reaction was stirred at 0° C. for 10 min. Water(2 mL) was added to quench the reaction, the resulting mixture wasfiltered and the residue was washed with ethyl acetate (20 mL×2). Thecombined filtrates were washed with brine (10 mL), dried over Na₂SO₄,and concentrated. The residue was purified by column chromatography(SiO₂, petroleum ether:ethyl acetate=2:1 to 1:1) followed bypurification by preparative HPLC to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((4-methylthiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(14 mg).

¹H NMR (Cloroform-d, 400 MHz) δ 8.26-8.24 (m, 1H), 8.18-8.17 (m, 1H),7.19 (s, 1H), 7.03-7.00 (m, 1H), 6.87 (s, 1H), 5.01-4.95 (m, 1H), 4.82(d, J=4.8 Hz, 2H), 4.47-4.42 (q, J=7.2 Hz, 2H), 2.66 (s, 3H), 2.48 (s,3H), 1.68 (d, J=6.4 Hz, 6H), 1.37 (t, J=7.2 Hz, 3H). LC-MS (m/z) 423.0(MH⁺); t_(R)=1.92 minutes (Method C).

The following examples were prepared in a similar manner:

SUPPORTING EXAMPLE S305-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 3-methyl-1,2,4-oxadiazole-5-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27 (dd, J=7.2, 2.0 Hz, 1H), 8.19-8.18(m, 1H), 7.17 (s, 1H), 7.05-7.02 (m, 1H), 4.95 (brs, 1H), 4.76 (d, J=4.8Hz, 2H), 4.49 (q, J=6.8 Hz, 2H), 2.65 (s, 3H), 2.44 (s, 3H), 1.67 (d,J=6.4 Hz, 6H), 1.42 (t, J=6.8 Hz, 3H). LC-MS (m/z) 408.2 (MH⁺);t_(R)=2.31 minutes (Method B).

SUPPORTING EXAMPLE S315-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 1-methyl-1H-1,2,4-triazole-3-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27 (dd, J=1.6, 7.2 Hz, 1H), 8.18 (dd,J=1.6, 4.8 Hz, 1H), 8.05 (s, 1H), 7.22 (s, 1H), 7.04-7.01 (m, 1H), 5.50(brs, 1H), 5.01-4.96 (m, 1H), 4.58 (d, J=4.8 Hz, 2H), 4.50 (q, J=7.2 Hz,2H), 3.95 (s, 3H), 2.66 (s, 3H),1.66 (d, J=6.0 Hz, 6H), 1.45 (t, J=7.2Hz, 3H). LC-MS (m/z) 407.1 (MH⁺); t_(R)=1.87 minutes (Method C).

SUPPORTING EXAMPLE S325-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 2-methylthiazole-5-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.17-8.25 (m, 1H), 8.19-8.18 (m, 1H),7.62 (s, 1H), 7.26 (s, 1H), 7.05-7.02 (m, 1H), 4.83-4.80 (m, 1H), 4.70(s, 2H), 4.48 (q, J=7.2 Hz, 2H), 2.71 (s, 3H), 2.65 (s, 3H), 1.62 (d,J=6.4 Hz, 6H), 1.40 (t, J=7.2 Hz, 3H). LC-MS (m/z) 423 (MH⁺); t_(R)=1.80minutes (Method A).

SUPPORTING EXAMPLE S335-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 5-methyl-1,3,4-thiadiazole-2-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.32-8.29 (m, 1H), 8.22-8.20 (m, 1H),7.30 (s, 1H), 7.07-7.04 (m, 1H), 5.51 (brs, 1H), 4.97 (d, J=5.2 Hz, 2H),4.57-4.48 (m, 2H), 2.82 (s, 3H), 2.69 (s, 3H), 1.69 (d, J=6.4 Hz, 6H),1.42 (t, J=7.2 Hz, 3H). LC-MS (m/z) 424 (MH⁺); t_(R)=2.14 minutes(Method B).

SUPPORTING EXAMPLE S345-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-3-thienyl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 5-methylthiophene-3-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.28-8.26 (m, 1H), 8.18-8.17 (m, 1H),7.22 (s, 1H), 7.04-7.01 (m, 2H), 6.80 (s, 1H), 4.84-4.77 (m, 1H), 4.66(brs, 1H), 4.48-4.43 (m, 4H), 2.65 (s, 3H), 2.51 (s, 3H), 1.62 (d, J=6.8Hz, 6H), 1.38 (t, J=7.2 Hz, 3H). LC-MS (m/z) 422 (MH⁺); t_(R)=2.21minutes (Method H).

SUPPORTING EXAMPLE S355-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methyl-2-thienyl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 4-methylthiophene-2-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27 (dd, J=7.6, 1.6 Hz, 1H), 8.18 (dd,J=4.8, 2.0 Hz, 1H), 7.26 (s, 1H), 7.04-7.01 (m, 1H), 6.92 (s, 1H), 6.87(s, 1H), 4.86-4.81 (m, 1H), 4.72 (brs, 1H), 4.66-4.65 (m, 2H), 4.47 (q,J=7.2 Hz, 2H), 2.65 (s, 3H), 2.27 (s, 3H), 1.62 (d, J=6.4 Hz, 6H), 1.39(t, J=7.2 Hz, 3H). LC-MS (m/z) 422.1 (MH⁺); t_(R)=1.78 minutes (MethodI).

SUPPORTING EXAMPLE S365-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-2-thienyl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 5-methylthiophene-2-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.28-8.25 (m, 1H), 8.18-8.17 (m, 1H),7.25 (s, 1H), 7.04-7.01 (m, 1H), 6.90-6.89 (m, 1H), 6.67-6.66 (s, 1H),4.86-4.81 (m, 1H), 4.72 (brs, 1H), 4.63-4.62 (m, 2H), 4.48 (q, J=6.8 Hz,2H), 2.65 (s, 3H), 2.49 (s, 3H), 1.62 (d, J=6.4 Hz, 6H), 1.39 (t, J=7.2Hz, 3H). LC-MS (m/z) 422 (MH⁺); t_(R)=1.78 minutes (Method I).

SUPPORTING EXAMPLE S375-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyloxazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 2-methyloxazole-4-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.26-8.24 (m, 1H), 8.17-8.16 (m, 1H),7.53 (s, 1H), 7.17 (s, 1H), 7.03-7.00 (m, 1H), 5.01 (brs, 1H), 4.88-4.83(m, 1H), 4.49-4.44 (m, 2H), 4.39 (d, J=5.2 Hz, 2H), 2.64 (s, 3H), 2.48(s, 3H), 1.62 (d, J=6.8 Hz, 6H), 1.38 (t, J=7.2 Hz, 3H). LC-MS (m/z)407.1 (MH⁺); t_(R)=2.03 minutes (Method C).

SUPPORTING EXAMPLE S385-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyloxazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 5-methyloxazole-2-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27-8.25 (m, 1H), 8.19-8.17 (m, 1H),7.17 (s, 1H), 7.04-7.01 (m, 1H), 6.75 (s, 1H), 5.41 (brs, 1H), 4.99-4.95(m, 1H), 4.55 (d, J=4.8 Hz, 2H), 4.49 (q, J=7.2 Hz, 2H), 2.65 (s, 3H),2.35 (s, 3H), 1.67 (d, J=6.4 Hz, 6H), 1.44 (t, J=7.2 Hz, 3H). LC-MS(m/z) 407.1 (MH⁺); t_(R)=2.06 minutes (Method C).

SUPPORTING EXAMPLE S395-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared from 1H-pyrazole-3-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.25-8.23 (m, 1H), 8.18-8.16 (m, 1H),7.58 (d, J=2.4 Hz, 1H), 7.19 (s, 1H), 7.03-7.00 (m, 1H), 6.35 (d, J=2.4Hz, 1H), 5.31 (brs, 1H), 4.93-4.87 (m, 1H), 4.57 (d, J=4.8 Hz, 2H),4.50-4.45 (m, 2H), 2.65 (s, 3H), 1.63 (d, J=6.4 Hz, 6H), 1.41 (t, J=7.2Hz, 3H). LC-MS (m/z) 392.1 (MH⁺); t_(R)=1.92 minutes (Method C).

SUPPORTING EXAMPLE S405-(2-ethoxy-3-pyridyl)-N-(1H-imidazol-4-ylmethyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared from 1H-imidazole-4-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.24-8.22 (m, 1H), 8.17-8.15 (m, 1H),7.65 (m, 1H), 7.19 (m, 1H), 7.03-7.00 (m, 2H), 5.27 (brs, 1H), 4.92-4.86(m, 1H), 4.49-4.44 (m, 4H), 2.64 (s, 3H), 1.61 (d, J=6.4 Hz, 6H), 1.40(t, J=7.2 Hz, 3H). LC-MS (m/z) 392.1 (MH⁺); t_(R)=1.52 minutes (MethodC).

SUPPORTING EXAMPLE S41N-benzyl-5-(2-ethoxy-3-pyridyl)-1-isopropyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared from benzaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.16-8.07 (m, 3H), 7.43-7.38 (m, 2H), 7.35(dd, J=8.4, 7.0 Hz, 2H), 7.27-7.21 (m, 1H), 7.04 (dd, J=7.4, 4.9 Hz,2H), 6.96 (s, 1H), 5.34 (hept, J=6.4 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H),4.23 (q, J=7.0 Hz, 2H), 1.56-1.45 (d, J=6.4 Hz , 6H), 1.13 (t, J=7.0 Hz,3H). LC-MS (m/z) 388 (MH⁺); t_(R)=0.66 minutes (Method D).

SUPPORTING EXAMPLE S425-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methylisoxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 3-methylisoxazole-5-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.25-8.17 (m, 3H), 7.16-7.11 (m, 2H), 7.08(t, J=5.8 Hz, 1H), 6.31 (s, 1H), 5.31 (hept, J=6.5 Hz, 1H), 4.71 (d,J=5.7 Hz, 2H), 4.40 (q, J=7.0 Hz, 2H), 2.23 (s, 3H), 1.56 (d, J=6.5 Hz,6H), 1.29 (t, J=7.0 Hz, 3H). LC-MS (m/z) 393.1 (MH⁺); t_(R)=0.55 minutes(Method D).

SUPPORTING EXAMPLE S435-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared from 5-methyl-1,2,4-oxadiazole-3-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.20-8.10 (m, 3H), 7.13 (s, 1H), 7.08 (dd,J=7.4, 4.9 Hz, 1H), 7.00 (t, J=5.9 Hz, 1H), 5.26 (hept, J=6.4 Hz, 1H),4.66 (d, J=5.8 Hz, 2H), 4.36 (q, J=7.0 Hz, 2H), 2.56 (s, 3H), 1.50 (d,J=6.4 Hz, 6H), 1.28 (t, J=7.0 Hz, 3H). LC-MS (m/z) 394 (MH⁺); t_(R)=0.54minutes (Method D).

SUPPORTING EXAMPLE S44N-[(1,5-dimethylpyrazol-3-yl)methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared from 1,5-dimethyl-1H-pyrazole-3-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Methanol-d₄, 600 MHz) δ 8.17 (dd, J=5.0, 2.0 Hz, 1H), 8.04 (s,1H), 7.94 (dd, J=7.3, 1.9 Hz, 1H), 7.07 (dd, J=7.3, 4.9 Hz, 1H), 6.98(s, 1H), 6.07 (s, 1H), 5.22 (hept, J=6.4 Hz, 1H), 4.53 (d, J=1.5 Hz,2H), 4.39 (q, J=7.0 Hz, 2H), 3.75 (s, 3H), 2.26 (s, 3H), 1.63 (d, J=6.5Hz, 6H), 1.30 (t, J=7.1 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺); t_(R)=0.60minutes (Method D).

SUPPORTING EXAMPLE S453-(1-isopropyl-3-methyl-7-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpyridin-2(1H)-one

Prepared from 1-methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) 8.28-8.26 (m, 1H), 8.19-8.18 (m, 1H),7.44-7.42 (m, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.19 (s, 1H), 7.05-7.02 (m,1H), 6.66 (d, J=9.6 Hz, 1H), 4.82-4.76 (m, 1H), 4.56 (brs, 1H),4.47-4.42 (m, 2H), 4.29 (d, J=5.2 Hz, 2H), 3.56 (s, 3H), 2.65 (s, 3H),1.62 (d, J=6.4 Hz, 6H), 1.35 (t, J=7.2 Hz, 3H). LC-MS (m/z) 433.1 (MH⁺);t_(R)=1.86 min (Method C).

SUPPORTING EXAMPLE S465-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((2-methyl-1H-imidazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from 2-methyl-1H-imidazole-4-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) 8.25-8.23 (m, 1H), 8.17-8.15 (m, 1H),7.19 (s, 1H), 7.02-6.99 (m, 1H), 6.89 (s, 1H), 5.19 (brs, 1H), 4.90-4.85(m, 1H), 4.49-4.41 (m, 4H), 2.63 (s, 3H), 2.43 (s, 3H), 1.61 (d, J=6.8Hz, 6H), 1.40 (t, J=7.2 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺); t_(R)=1.60 min(Method C).

SUPPORTING EXAMPLE S475-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((5-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared from 5-methyl-1H-pyrazole-3-carbaldehyde and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27-8.25 (m, 1H), 8.19-8.17 (m, 1H),7.20 (s, 1H), 7.04-7.01 (m, 1H), 6.08 (s, 1H), 5.29 (brs, 1H), 4.94-4.87(m, 1H), 4.51-4.46 (m, 4H), 2.65 (s, 3H), 2.35 (s, 3H), 1.63 (d, J=6.8Hz, 6H), 1.42 (t, J=7.2 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺); t_(R)=1.90 min(Method B).

SUPPORTING EXAMPLE S485-(2-ethoxypyridin-3-yl)-1-ethyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from (1-methyl-1H-pyrazol-4-yl)methanamine and5,7-dibromo-1-ethyl-3-methyl-1H-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.28-8.26 (m, 1H), 8.19-8.17 (m, 1H),7.56 (s, 1H), 7.43 (s, 1H), 7.23 (s, 1H), 7.04-7.01 (m, 1H), 4.53 (brs,1H), 4.50-4.45 (m, 4H), 4.40 (d, J=4.8 Hz, 2H), 3.92 (s, 3H), 2.63 (s,3H), 1.47 (t, J=7.2 Hz, 3H), 1.39 (t,1 =7.2 Hz, 3H). LC-MS: LC-MS (m/z)392.1 (MH⁺); t_(R)=1.72 min (Method F).

SUPPORTING EXAMPLE S493-(1-isopropyl-3-methyl-7-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpyridin-2(1H)-one

A mixture of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(60 mg, 0.17 mmol), 3-bromo-1-methylpyridin-2(1H)-one (62 mg, 0.33mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride(24 mg, 33 mmol), Cs₂CO₃ (108 mg, 0.33 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (84 mg, 0.33mmol) in dioxane (3 mL) was degassed and purged with N₂ 3 times, andthen the mixture was stirred at 100° C. for 1 hour under microwaveirradiation. Then water (30 mL) was added and the mixture was extractedwith ethyl acetate (30 mL×3). The combined organic layers were washedwith brine (20 mL), dried over Na₂SO₄ and concentrated. The crudeproduct was purified by preparative HPLC to give3-(1-isopropyl-3-methyl-7-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-1H-pyrazolo[4,3-b]pyridin-5-yl)-1-methylpyridin-2(1H)-one.

¹H NMR (Cloroform-d, 400 MHz) δ 8.45-8.42 (m, 1H), 7.82-7.80 (m, 1H),7.56-7.54 (m, 2H), 7.44-7.43 (m, 1H), 6.43-6.41 (m, 1H), 4.84-4.82 (m,1H), 4.48 (s, 2H), 3.92 (s, 3H), 3.68 (s, 3H), 2.63 (s, 3H) 1.57 (d,J=6.8 Hz, 6H). LC-MS (m/z) 392.1 (MH⁺); t_(R)=1.76 min (Method B).

SUPPORTING EXAMPLE S505-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((4-methyloxazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine2,2,2-trifluoroacetate

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 4-methyloxazole-2-carbaldehyde.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.37 (dd, J=4.9, 1.9 Hz, 1H), 8.03 (dd,J=7.5, 1.9 Hz, 1H), 7.81 (s, 1H), 7.22 (dd, J=7.5, 4.9 Hz, 1H), 7.11 (s,1H), 6.64 (bds, 1H), 5.29 (p, J=6.3 Hz, 1H), 4.91 (d, J=5.6 Hz, 2H),4.37 (q, J=7.0 Hz, 2H), 2.54 (s, 3H), 2.03 (s, 3H), 1.50 (d, J=6.3 Hz,6H), 1.26 (t, J=7.0 Hz, 3H). LC-MS (m/z) 407.4 (MH⁺); t_(R)=0.52 minutes(Method E).

SUPPORTING EXAMPLE S51N-((1,2-dimethyl-1H-imidazol-4-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine2,2,2-trifluoroacetate

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1,2-dimethylimidazole-4-carbaldehyde.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.61 (s, 1H),7.23-7.17 (m, 1H), 7.09 (s, 1H), 6.66 (bds, 1H), 5.30 (m, 1H), 4.85 (m,2H), 4.36 (q, J=7.0 Hz, 2H), 3.77 (s, 3H), 2.58 (s, 3H), 2.53 (s, 3H),1.50 (d, J=6.3 Hz, 6H), 1.19 (t, J=7.0 Hz, 3H). LC-MS (m/z) 420.4 (MH⁺);t_(R)=0.33 minutes (Method E).

SUPPORTING EXAMPLE S525-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-methyl-1,2,4-oxadiazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27-8.25 (m, 1H), 8.19-8.18 (m ,1H),7.23 (s, 1H), 7.04-7.01 (m, 1H), 5.23 (brs, 1H), 4.94-4.91 (m, 1H), 4.63(d, J=5.2 Hz, 2H), 4.52-4.47 (m, 2H), 2.65 (s, 3H), 2.64 (s, 3H), 1.66(d, J=6.4 Hz, 6H), 1.44 (t, J=6.8 Hz, 3H). LC-MS (m/z) 408.4 (MH⁺);t_(R)=0.49 minutes (Method E).

SUPPORTING EXAMPLE S535-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1,2,4-oxadiazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1,2,4-oxadiazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz) δ 8.78 (s, 1H), 8.27-8.25 (m, 1H),8.19-8.17 (m, 1H), 7.25 (s, 1H), 7.04-7.01 (m, 1H), 5.25 (brs, 1H),4.96-4.90 (m, 1H), 4.74 (d, J=4.4 Hz, 2H), 4.52-4.47 (m, 2H), 2.65 (s,3H), 1.66 (d, J=6.4 Hz, 6H), 1.43 (t, J=7.2 Hz, 3H). LC-MS (m/z) 394.4(MH⁺); t_(R)=0.47 minutes (Method E).

SUPPORTING EXAMPLE S54N-[(1,5-dimethylpyrazol-3-yl)methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1,5-dimethylpyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz) δ 8.26 (dd, J=2.0, 7.6 Hz, 1H), 8.18 (dd,J=2.0, 8.4 Hz, 1H), 7.18 (s, 1H), 7.03 (dd, J=5.2, 7.6 Hz, 1H), 6.03 (s,1H), 5.29 (brs, 1H), 4.95-4.88 (m, 1H), 4.51-4.44 (m, 4H), 3.79 (s, 3H),2.65 (s, 3H), 2.29 (s, 3H), 1.64 (d, J=6.8 Hz, 6H), 1.42 (t, J=7.6 Hz,3H). LC-MS (m/z) 420.4 (MH⁺); t_(R)=0.53 minutes (Method E).

SUPPORTING EXAMPLE S555-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1H-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-methyl-1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz) δ 8.23 (dd, J=2.0, 7.6 Hz, 1H), 8.17 (dd,J=2.0, 5.2 Hz, 1H), 7.19 (s, 1H), 7.01 (dd, J=5.2, 7.6 Hz, 1H), 5.70(brs, 1H), 5.00 (brs, 1H), 4.61 (br s, 2H), 4.48 (q, J=7.2 Hz, 2H), 2.64(s, 3H), 2.48 (s, 3H), 1.65 (d, J=6.4 Hz, 6H), 1.43 (t, J=7.2 Hz, 3H).LC-MS (m/z) 407.1 (MH⁺); t_(R)=1.86 minutes (Method C).

SUPPORTING EXAMPLE S565-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-methyl-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz) δ 8.24-8.17 (m, 3H), 8.06 (s, 1H), 7.23(s, 1H), 7.04-7.01 (m, 1H), 5.61 (brs, 1H), 5.08-5.01 (m, 1H), 4.60 (d,J=4.4 Hz, 2H), 4.50 (q, J=7.2 Hz, 2H), 3.95 (s, 3H), 1.70 (d, J=6.4 Hz,6H), 1.46 (t, J=7.2 Hz, 3H). LC-MS (m/z) 393.4 (MH⁺); t_(R)=0.41 minutes(Method E).

SUPPORTING EXAMPLE S575-(2-ethoxy-3-pyridyl)-1-isopropyl-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz) δ 8.23-8.17 (m, 3H), 7.61 (d, J=2.4 Hz,1H), 7.22 (s, 1H), 7.04-7.01 (m, 1H), 6.38 (d, J=2.4 Hz, 1H), 5.46 (brs,1H), 5.02-4.95 (m, 1H), 4.59 (d, J=4.4 Hz, 2H), 4.49 (q, J=7.2 Hz, 2H),1.67 (d, J=6.8 Hz, 6H), 1.43 (t, J=7.2 Hz, 3H). LC-MS (m/z) 378.3 (MH⁺);t_(R)=0.43 minutes (Method E).

SUPPORTING EXAMPLE S585-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((1-methyl-1H-imidazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine2,2,2-trifluoroacetate

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine and(1-methyl-1H-imidazol-4-yl)methanamine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.99 (s, 1H), 8.55 (bds, 1H), 8.39 (dd,J=5.0, 1.9 Hz, 1H), 8.02 (dd, J=7.4, 1.9 Hz, 1H), 7.67 (s, 1H), 7.23(dd, J=7.4, 5.0 Hz, 1H), 7.04 (s, 1H), 5.29 (p, J=6.4 Hz, 1H), 4.91 (d,J=5.8 Hz, 2H), 4.36 (t, J=7.0 Hz, 2H), 3.82 (s, 3H), 2.55 (s, 3H), 1.51(d, J=6.4 Hz, 6H), 1.21 (t, J=7.0 Hz, 3H). LC-MS (m/z) 406.4 (MH⁺);t_(R)=0.34 minutes (Method E).

SUPPORTING EXAMPLE S595-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1,3,4-oxadiazol-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine and(1,3,4-oxadiazol-2-yl)methanamine hydrobromide.

¹H NMR (Chloroform-d, 400 MHz) δ 8.42-8.37 (m, 2H), 8.24-8.22 (m, 1H),7.88 (s, 1H), 7.10-7.08 (m, 2H), 4.86-4.79 (m, 1H), 4.52 (d, J=7.2 Hz,2H), 4.33 (s, 2H), 2.71 (s, 3H), 1.55 (d, J=6.8 Hz, 6H), 1.45 (t, J=7.2Hz, 3H). LC-MS (m/z) 394.3 (MH⁺); t_(R)=0.61 minutes (Method E).

SUPPORTING EXAMPLE S605-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine and(1-methyl-1H-pyrazol-3-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27-8.25 (m, 1H), 8.18-8.17 (m, 1H),7.37 (d, J=2.0 Hz, 1H), 7.20 (s, 1H), 7.04-7.01 (m, 1H), 6.26 (d, J=2.0Hz, 1H), 5.25 (brs, 1H), 4.95-4.88 (m, 1H), 4.51-4.46 (m, 4H), 3.93 (s,3H), 2.65 (s, 3H), 1.64 (d, J=6.4 Hz, 6H), 1.42 (t, J=6.8 Hz, 3H). LC-MS(m/z) 406.4 (MH⁺); t_(R)=0.50 minutes (Method E).

SUPPORTING EXAMPLE S615-(1,3-dimethylpyrazol-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from5-chloro-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amineand1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole.

¹H NMR (Chloroform-d, 400 MHz): δ 7.75 (s, 1H), 7.55 (s, 1H), 7.40 (s,1H), 6.56 (s, 1H), 4.74-4.67 (m, 1H), 4.54 (brs, 1H), 4.37 (d, J=4.8 Hz,2H), 3.92 (s, 3H), 3.87 (s, 3H), 2.60 (s, 3H), 2.50 (s, 3H), 1.56 (d,J=6.4 Hz, 6H). LC-MS (m/z) 379.4 (MH⁺); t_(R)=0.38 minutes (Method E).

SUPPORTING EXAMPLE S621-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from5-chloro-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amineand (2-methoxy-3-pyridyl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz) δ 8.21-8.17 (m, 2H), 7.57 (s, 1H), 7.45(s, 1H), 7.08-7.04 (m, 2H), 4.79-4.73 (m, 1H), 4.57 (brs, 1H), 4.39 (d,J=4.8 Hz, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 2.64 (s, 3H), 1.59 (d, J=6.4Hz, 6H). LC-MS (m/z) 392.4 (MH⁺); t_(R)=0.43 minutes (Method E).

SUPPORTING EXAMPLE S631-isopropyl-5-(2-methoxyphenyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from5-chloro-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amineand (2-methoxyphenyl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz) δ 7.74 (dd, J=1.8, 7.4 Hz, 1H), 7.56 (s,1H), 7.43 (s, 1H), 7.40-7.31 (m, 1H), 7.13-7.05 (m, 1H), 7.00 (d, J=8.0Hz, 1H), 6.94 (s, 1H), 4.82-4.72 (m, 1H), 4.53 (brs, 1H), 4.36 (d, J=4.8Hz, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 2.65 (s, 3H), 1.59 (d, J=6.8 Hz,6H). LC-MS (m/z) 391.1 (MH⁺); t_(R)=0.47 minutes (Method E).

SUPPORTING EXAMPLE S641-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-phenyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from5-chloro-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amineand phenylboronic acid.

¹H NMR (Chloroform-d, 400 MHz) δ 8.00-7.99 (m, 2H), 7.58 (s, 1H),7.49-7.43 (m, 3H), 7.41-7.37 (m, 1H), 6.88 (s, 1H), 4.79-4.69 (m, 1H),4.56 (brs, 1H), 4.43 (d, J=4.8 Hz, 2H), 3.93 (s, 3H), 2.67 (s, 3H), 1.59(d, J=6.4 Hz, 6H). LC-MS (m/z) 361.3 (MH⁺); t_(R)=0.45 minutes (MethodE).

SUPPORTING EXAMPLE S651-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(2-methyl-3-thienyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from5-chloro-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amineand 4,4,5,5-tetramethyl-2-(2-methyl-3-thienyl)-1,3,2-dioxaborolane.

¹H NMR (Chloroform-d, 400 MHz) δ 7.55 (s, 1H), 7.40 (s, 1H), 7.26 (d,JJJ=4.8 Hz 1H), 7.08 (d, JJJ=5.2 Hz 1H), 6.60 (brs, 1H), 4.77-4.72 (m,1H), 4.57 (brs, 1H), 4.36 (d, J=4.4 Hz, 2H), 3.92 (s, 3H), 2.66 (s, 3H),2.62 (s, 3H), 1.58 (d, J=6.4 Hz, 6H)). LC-MS (m/z) 381.0 (MH⁺);t_(R)=2.06 minutes (Method F).

SUPPORTING EXAMPLE S665-(1,5-dimethylpyrazol-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from5-chloro-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-13]pyridin-7-amineand 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yppyrazole.

¹H NMR (DMSO-d₆, 400 MHz) δ 7.74 (s, 1H), 7.64 (s, 1H), 7.44 (s, 1H),6.57 (brs, 1H), 6.57 (s, 1H), 5.13-5.07 (m, 1H), 4.38 (d, J=5.2 Hz, 2H),3.76 (s, 3H), 3.75 (s, 3H), 2.56 (s, 3H), 2.41 (s, 3H), 1.42 (d, J=6.4Hz, 6H). LC-MS (m/z) 379.4 (MH⁺); t_(R)=0.38 minutes (Method E).

SUPPORTING EXAMPLE S675-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example 1,from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2, (2-ethoxy-3-pyridyl)boronic acid and(1-methyl-1H-pyrazol-3-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27 (dd, J=1.6, 7.2 Hz, 1H), 8.17 (dd,J=1.6, 4.8 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.21 (s, 1H), 7.02 (dd,J=4.8, 7.6 Hz, 1H), 6.25 (d, J=2.0 Hz, 1H), 5.24 (brs, 1H), 4.65-4.60(m, 1H), 4.51-4.46 (m, 4H), 3.92 (s, 3H), 2.65 (s, 3H), 2.22-2.15 (m,1H), 1.92-1.85 (m, 1H), 1.62 (d, J=6.4 Hz, 3H), 1.43 (t, J=6.8 Hz, 3H),0.92 (t, J=7.6 Hz, 3H). LC-MS (m/z) 420.1 (MH⁺); t_(R)=1.87 (Method A).

SUPPORTING EXAMPLE S683-methyl-1-[1-methylpropyl]-N-[(2-methyltetrazol-5-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example 1,from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and (2-methyl-2H-tetrazol-5-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.27 (dd, J=7.50, 1.98 Hz, 1H) 8.19(dd, J=5.07, 1.98 Hz, 1H) 7.25 (s, 1H) 7.03 (dd, J=7.39, 4.96 Hz, 1H)5.29 (s, 1H) 4.78 (d, J=5.07 Hz, 2H) 4.61-4.68 (m, 1H) 4.37-4.41 (m, 5H)2.66 (s, 3H) 2.18 (s, 1H) 1.80-1.96 (m, 3H) 1.65 (d, J=6.62 Hz, 3H) 1.06(t, J=7.39 Hz, 3H) 0.92 (t, J=7.39 Hz, 3H). LC-MS (m/z) 436.1 (MH⁺);t_(R)=1.97 (Method A).

SUPPORTING EXAMPLE S695-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared using the same procedure as described for supporting example 1,from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1, (2-ethoxy-3-pyridyl)boronic acid and(1-methyl-1H-pyrazol-4-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.18-8.14 (m, 2H), 8.11 (s, 1H), 7.59(s, 1H), 7.40 (s, 1H), 7.11-7.07 (m, 2H), 6.73-6.72 (m, 1H), 5.01-4.96(m, 1H), 4.39-4.33 (m, 4H), 3.77 (s, 3H), 2.00-1.97 (m, 1H), 1.81-1.79(m, 1H), 1.49 (d, J=6.8 Hz, 3H), 1.25 (t, J=6.8 Hz, 3H), 0.73 (t, J=7.2Hz, 3H). SFC-MS: t_(R)=4.72 min, ee %=97.51. LC-MS (m/z) 406.1 (MH⁺);t_(R)=2.09 (Method A).

SUPPORTING EXAMPLE S705-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example 1,from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2, (2-ethoxy-3-pyridyl)boronic acid and(1-methyl-1H-pyrazol-4-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.17-8.14 (m, 2H), 8.11 (s, 1H), 7.59(s, 1H), 7.40 (s, 1H), 7.11-7.06 (m, 2H), 6.74-6.71 (m, 1H), 5.01-4.97(m, 1H), 4.39-4.33 (m, 4H), 3.77 (s, 3H), 2.00-1.95 (m, 1H), 1.82-1.77(m, 1H), 1.49 (d, J=6.4 Hz, 3H), 1.25 (t, J=6.8 Hz, 3H), 0.73 (t, J=7.2Hz, 3H). SFC-MS: t_(R)=4.48 min, ee %=95.47. LC-MS (m/z) 406.1 (MH⁺);t_(R)=2.01 (Method A).

SUPPORTING EXAMPLE S715-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine,2-ethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and(4-methylthiazol-5-yl)methanamine dihydrochloride.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.84 (s, 1H), 8.17 (dd, J=4.9, 1.9 Hz, 1H),8.14-8.08 (m, 2H), 7.07 (dd, J=7.3, 4.7 Hz, 2H), 7.02 (s, 1H), 5.26(hept, J=6.4 Hz, 1H), 4.67 (d, J=5.3 Hz, 2H), 4.34 (q, J=7.0 Hz, 2H),2.44 (s, 3H), 1.50 (d, J=6.3 Hz, 6H), 1.21 (t, J=7.0 Hz, 3H). LC-MS(m/z) 409.5 (MH⁺); t_(R)=0.51 (Method D).

SUPPORTING EXAMPLE S725-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]oxymethyl]-2-methyl-oxazole

Prepared using the same procedure as described for supporting example 1,from 5,7-dibromo-1-isopropyl-1H-pyrazolo[4,3-b]pyridine,2-ethoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and(2-methyloxazol-5-yl)methanol.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.24 (dd, J=4.9, 2.0 Hz, 1H), 8.18 (dd,J=7.3, 2.0 Hz, 1H), 7.65 (s, 1H), 7.28 (s, 1H), 7.14 (dd, J=7.4, 4.9 Hz,1H), 5.45 (s, 2H), 5.11 (hept, J=6.7 Hz, 1H), 4.45 (q, J=7.0 Hz, 2H),2.51 (s, 3H), 2.43 (s, 3H), 1.44 (d, J=6.6 Hz, 6H), 1.36 (t, J=7.0 Hz,3H). LC-MS (m/z) 408.6 (MH⁺); t_(R)=0.64 (Method D).

SUPPORTING EXAMPLE S735-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrimidin-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and pyrimidin-4-ylmethanamine.

¹H NMR (400 MHz, Chloroform-d,) δ 9.28 (s, 1H), 8.76 (d, J=5.3 Hz, 1H),8.27 (brd, J=7.5 Hz, 1H), 8.19 (brd, J=3.3 Hz, 1H), 7.45 (brs, 1H), 7.11(s, 1H), 7.04 (dd, J=5.0, 6.9 Hz, 1H), 6.30 (weak br s, 1H), 5.11 (m,1H), 4.68 (m, 2H), 4.46 (q, J=7.1 Hz, 2H), 2.68 (s, 3H), 1.72 (d, J=6.6Hz, 6H), 1.39 (t, J=7.1 Hz, 3H). LC-MS (m/z) 404.1 (MH⁺); t_(R)=1.89(Method C).

SUPPORTING EXAMPLE S745-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrimidin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and pyrimidin-2-ylmethanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.83 (d, J=4.8 Hz, 2H), 8.28 (dd,J=2.0, 7.2 Hz, 1H), 8.19 (dd, J=2.0, 4.8 Hz, 1H), 7.34-7.31 (m, 1H),7.19 (s, 1H), 7.03 (dd, 1 =5.2, 7.6 Hz, 1H), 6.45 (brs, 1H), 5.17-5.10(m, 1H), 4.74 (d, J=4.0 Hz, 2H), 4.50 (q, J=6.8 Hz, 2H), 2.67 (s, 3H),1.72 (d, J=6.4 Hz, 6H), 1.46 (t, J=6.8 Hz, 3H). LC-MS (m/z) 404 (MH⁺);t_(R)=2.20 (Method B).

SUPPORTING EXAMPLE S755-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methylpyrimidin-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and(4-methylpyrimidin-2-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.65 (d, J=5.2 Hz, 1H), 8.25 (dd,J=2.0, 7.2 Hz, 1H), 8.18 (dd, J=2.0, 5.2 Hz, 1H), 7.18-7.15 (m, 2H),7.03 (dd, J=5.2, 7.2 Hz, 1H), 6.57 (brs, 1H), 5.21-5.15 (m, 1H), 4.68(d, J=4.0 Hz, 2H), 4.50 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.61 (s, 3H),1.73 (d, J=6.4 Hz, 6H), 1.46 (t, J=7.2 Hz, 3H). LC-MS (m/z) 418.1 (MH⁺);t_(R)=2.2 (Method C).

SUPPORTING EXAMPLE S765-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrazin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and pyrazin-2-ylmethanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.73 (d, J=1.6 Hz, 1H), 8.63 (dd,J=2.4, 1.6 Hz, 1H), 8.59 (d, J=2.4 Hz, 1H), 8.26 (dd, J=2, 7.6 Hz, 1H),8.18 (dd, J=2, 4.8 Hz, 1H), 7.18 (s, 1H), 7.05-7.02 (m, 1H), 6.10 (brs,1H), 5.06-5.03 (m, 1H), 4.7 (d, J=4.0 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H),2.67 (s, 3H), 1.69 (d, J=6.4 Hz, 6H), 1.42 (t, J=7.2 Hz, 3H). LC-MS(m/z) 404.1 (MH⁺); t_(R)=2.19 (Method B).

SUPPORTING EXAMPLE S775-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and(2-(trifluoromethyl)pyridin-3-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.67-8.66 (m, 1H), 8.26-8.23 (m, 1H),8.16-8.13 (m, 1H), 7.99-7.98 (m, 1H), 7.52-7.49 (m, 1H), 7.06 (s, 1H),7.02-6.99 (m, 1H), 4.94-4.87 (m, 4H), 4.34-4.29 (m, 2H), 2.66 (s, 3H),1.66 (d, J=6.4 Hz, 6H), 1.17 (t, J=7.2 Hz, 3H). LC-MS (m/z) 471 (MH⁺);t_(R)=2.1 (Method A).

SUPPORTING EXAMPLE S784-[[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]amino]methyl]-1-methyl-pyridin-2-one

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and4-(aminomethyl)-1-methylpyridin-2(1H)-one.

¹H NMR (Chloroform-d, 400 MHz) δ 8.23 (dd, J=1.6, 5.6 Hz, 1H), 8.16 (dd,J=2.0, 5.2 Hz, 1H), 7.29 (d, J=6.8 Hz, 1H), 7.04-7.01 (m, 2H), 6.61 (s,1H), 6.21 (d, J=6.8 Hz, 1H), 4.89 (m, 1H), 4.44-4.39 (m, 4H), 3.54 (s,3H), 2.65 (s, 3H), 1.66 (d, J=6.4 Hz, 6H), 1.33 (t, J=7.2 Hz, 3H). LC-MS(m/z) 433.1 (MH⁺); t_(R)=1.88 (Method B).

SUPPORTING EXAMPLE S795-(2-(ethylamino)pyridin-3-yl)-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineandN-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine.

¹H NMR (Chloroform-d, 600 MHz) δ 9.34-9.27 (m, 1H), 8.16 (dd, J=4.9, 1.8Hz, 1H), 7.77 (dd, J=7.6, 1.8 Hz, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 6.80(s, 1H), 6.58 (dd, J=7.5, 4.9 Hz, 1H), 4.72 (hept, J=6.6 Hz, 1H), 4.57(t, J=5.0 Hz, 1H), 4.41 (d, J=4.7 Hz, 2H), 3.93 (s, 3H), 3.57 (qd,J=7.2, 4.6 Hz, 2H), 2.61 (s, 3H), 1.59 (d, J=6.5 Hz, 6H), 1.37 (t, J=7.2Hz, 3H). LC-MS (m/z) 405.6 (MH⁺); t_(R)=0.45 minutes (Method D)

SUPPORTING EXAMPLE S815-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (4-methoxypyridin-2-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.45 (d, J=2.4 Hz, 1H), 8.26 (d, J=7.2Hz, 1H), 8.18 (d, J=4.4 Hz, 1H), 7.12 (s, 1H), 7.03 (dd, J=5.2, 6.8 Hz,1H), 6.87-6.81 (m, 2H), 6.54-6.49 (m, 1H), 5.13-5.06 (m, 1H), 4.57-4.55(m, 2H), 4.50-4.45 (m, 2H), 3.89 (s, 3H), 2.67 (s, 3H), 1.69 (d, J=6.4Hz, 6H), 1.42 (t, J=1.6 Hz, 3H). LC-MS (m/z) 433.1 (MH⁺); t_(R)=2.32(Method B).

SUPPORTING EXAMPLE S825-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxypyrazin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (6-methoxypyrazin-2-yl)methanaminehydrochloride.

¹H NMR (Chloroform-d, 400 MHz) δ 8.25-8.27 (m, 2H), 8.23 (s, 1H),8.18-8.19 (m, 1H), 7.21 (s, 1H), 7.03 (dd, J=5.2, 7.6 Hz 1H), 5.72-5.74(m, 1H), 4.99-5.06 (s, 1H), 4.60 (d, J=4.4 Hz 2H), 4.45-4.51 (m, 2H),4.03 (s, 3H), 2.66 (s, 3H), 1.67 (d, J=6.4 Hz, 6H), 1.42 (t, J=7.0 Hz,3H). LC-MS (m/z) 434.1 (MH⁺); t_(R)=1.86 (Method A).

SUPPORTING EXAMPLE S835-(2-ethoxy-3-pyridyl)-N-[(5-fluoropyrimidin-2-yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and(5-fluoropyrimidin-2-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.70 (s, 2H), 8.27 (dd, J=2.0, 6.0 Hz,1H), 8.20 (d, J=2.8 Hz, 1H), 7.18 (s, 1H), 7.04 (dd, J=4.8, 7.2 Hz, 1H),6.25 (brs, 1H), 5.13-5.06 (m, 1H), 4.75 (d, J=4.4 Hz, 2H), 4.50 (q J=7.2Hz, 2H), 3.69 (s, 3H), 1.71 (d, J=6.8 Hz, 6H), 1.46 (t, J=7.2 Hz, 3H)LC-MS (m/z) 422.1 (MH⁺); t_(R)=2.2 (Method C).

Supporting exemple S845-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (2-methylpyridin-3-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ =8.50 (d, J=5.2 Hz, 1H), 8.26 (d,J=7.2 Hz, 1H), 8.16 (d, J=5.2 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.19-7.16(m, 1H), 7.14 (s, 1H), 7.03-7.00 (m, 1H), 4.83-4.78 (m, 1H), 4.68 (brs,1H), 4.54 (d, J=5.2 Hz, 2H), 4.36 (q, J=7.2 Hz, 2H), 2.66 (s, 6H), 1.62(d, J=6.4 Hz, 6H), 1.25 (t, J=6.8 Hz, 3H) LC-MS (m/z) 417.1 (MH⁺);t_(R)=1.33 (Method A).

SUPPORTING EXAMPLE S855-(2-ethoxy-3-pyridyl)-N-[(2-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (2-fluoropyridin-3-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26-8.14 (m, 1H), 8.19-8.15 (m, 2H),7.90-7.80 (m, 1H), 7.22-7.19 (m, 1H), 7.13 (s, 1H), 7.03-7.00 (m, 1H),5.00-4.80 (m, 2H), 4.67-4.66 (m, 2H), 4.37 (q, J=7.2 Hz, 2H), 2.65 (s,3H), 1.65 (d, J=6.8 Hz, 6H), 1.33 (t, J=7.2 Hz, 3H) LC-MS (m/z) 421.1(MH⁺); t_(R)=1.8 (Method A).

SUPPORTING EXAMPLE S865-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (2-methoxypyridin-3-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26-8.23 (m, 1H), 8.16-8.13 (m, 2H),7.62-7.61 (m, 1H), 7.15 (s, 1H), 7.03-7.00 (m, 1H), 6.92-6.89 (m, 1H),5.13-5.11 (m, 1H), 4.93-4.90 (m, 1H), 4.53-4.52 (m, 2H), 4.41 (q, J=7.2Hz, 2H), 4.04 (s, 3H), 2.65 (s, 3H), 1.65 (d, J=6.8 Hz, 6H), 1.33 (t,J=7.2 Hz, 3HChloroform-d,400 MHz). LC-MS (m/z) 433 (MH⁺); t_(R)=2.04(Method A).

SUPPORTING EXAMPLE S875-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(6-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (6-methylpyridin-3-yl)methanamine¹H NMR (Chloroform-d, 400 MHz): δ =8.60 (s, 1H), 8.25 (brd, J=7.7 Hz,1H), 8.17 (brd, J=4.6 Hz, 1H), 7.66 (brd, J=8.4 Hz, 1H), 7.20-7.17 (m,1H), 7.20 (brd, J=11.5 Hz, 1H), 7.06-6.99 (m, 1H), 4.82 (s, 1H), 4.71(s, 1H), 4.55 (br s, 2H), 4.42 (q, J=7.1 Hz, 2H), 2.65 (s, 3H), 2.59 (s,3H), 1.62 (d, J=6.4 Hz, 6H), 1.33 (t, J=7.1 Hz, 3H). LC-MS (m/z) 417.1(MH⁺); t_(R)=1.36 (Method A).

SUPPORTING EXAMPLE S885-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2-methoxyphenyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (2-methoxyphenyl)methanamine.

¹H NMR (400 MHz, Chloroform-d,) δ =8.24 (d, J=7.3 Hz, 1H), 8.18-8.13 (m,1H), 7.37-7.30 (m, 2H), 7.23 (s, 1H), 7.03-6.94 (m, 3H), 5.08 (brs, 1H),4.89-4.81 (m, 1H), 4.53 (d, J=5.3 Hz, 2H), 4.45 (q, J=6.9 Hz, 2H), 3.90(s, 3H), 2.64 (s, 3H), 1.62 (d, J=6.6 Hz, 6H), 1.38 (t, J=7.1 Hz, 3H).LC-MS (m/z) 432.1 (MH⁺); t_(R)=2.19 (Method A).

SUPPORTING EXAMPLE S895-(2-ethoxy-3-pyridyl)-N-[(2-fluorophenyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (2-fluorophenyl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ =8.26-8.24 (m, 1H), 8.18-8.17 (m, 1H),7.44 (br s, J=7.7 Hz, 1H), 7.34-7.32 (m, 1H), 7.20 (s, 1H), 7.18-7.14(m, 2H), 7.03-7.02 (m, 1H), 4.89-4.85 (m, 2H), 4.65-4.64 (m, 2H), 4.42(q, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.64 (d, J=6.4 Hz, 6H), 1.33 (t, J=6.8Hz, 3H). LC-MS (m/z) 420 (MH⁺); t_(R)=2.14 (Method A)

SUPPORTING EXAMPLE S905-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[2-(trifluoromethyl)phenyl]methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and(2-(trifluoromethyl)phenyl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.34-8.22 (m, 1H), 8.17-8.15 (m, 1H),7.75 (d, J=7.6 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.55 (t, J=6.4 Hz, 1H),7.45 (t, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.03-6.99 (m, 1H), 4.91-4.86 (m,1H), 4.82 (br s, 2H), 4.35 (q, J=7.2 Hz, 2H), 2.66 (s, 3H), 1.62 (d,J=6.4 Hz, 6H), 1.23 (t, J=6.8 Hz, 3H). LC-MS (m/z) 470 (MH⁺); t_(R)=1.87(Method I)

SUPPORTING EXAMPLE S915-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methoxypyrazin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (3-methoxypyrazin-2-yl)methanaminehydrochloride.

¹H NMR (Chloroform-d, 400 MHz): δ 8.34-8.32 (m, 1H), 8.20-8.12 (m, 3H),7.30 (s, 1H), 7.04 (dd, J=7.6, 4.8 Hz, 1H), 6.53 (brs, 1H), 5.14-5.08(m, 1H), 4.58 (d, J=4.0 Hz 2H), 4.52 (q, J=7.2 Hz, 2H), 4.08 (s, 3H),2.67 (s, 3H), 1.71 (d, J=6.8 Hz, 6H), 1.51 (t, J=7.2 Hz, 3H). LC-MS(m/z) 434.1 (MH⁺); t_(R)=2.01 (Method A).

SUPPORTING EXAMPLE S925-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (4-methoxy-3-pyridyl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ=8.53-8.50 (m, 2H), 8.24 (dd, J=1.6, 7.2Hz, 1H), 8.17 (dd, J=2.8, 4.8 Hz, 1H), 7.23 (s, 1H), 7.05-7.00 (m, 1H),6.89 (d, J=6.0 Hz, 1H), 4.95 (brs, 1H), 4.87-4.81 (m, 1H), 4.54 (d,J=6.4 Hz, 2H), 4.47 (q,J=7.8 Hz, 2H), 3.95 (s, 3H), 2.65 (s, 3H), 1.62(d, J=6.4 Hz, 6H), 1.39 (t, J=7.8 Hz, 3H). LC-MS (m/z) 433.1 (MH⁺);t_(R)=1.39 (Method A).

SUPPORTING EXAMPLE S931-isopropyl-3-methyl-N-[(2-methyltetrazol-5-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,(2-propoxy-3-pyridyl)boronic acid and(2-methyl-2H-tetrazol-5-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ=8.26-8.19 (m, 2H), 7.22 (s, 1H),7.06-7.03(m, 1H), 5.48 (br. s, 1H), 4.99-4.91 (m, 1H), 4.81 (d, J=3.2Hz, 2H), 4.41-4.38 (m, 5H), 2.65 (s, 3H), 1.88-1.82 (m, 2H), 1.67 (d,J=6.4 Hz, 6H) 1.06 (t, J=7.2 Hz, 3H). LC-MS (m/z) 422.1 (MH⁺);t_(R)=2.04 (Method C).

SUPPORTING EXAMPLE S941-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine,2-propoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and(1-methyl-1H-pyrazol-4-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26 (dd, J=2.0, 7.6 Hz, 1H), 8.18 (d,J=5.2 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 1H), 7.22 (s, 1H), 7.03 (dd,J=4.8, 7.2 Hz, 1H), 4.84-4.67 (m, 1H), 4.48 (brs, 1H), 4.40-4.33 (m,4H), 3.94 (s, 3H), 2.65 (s, 3H), 1.89-1.74 (m, 2H), 1.59 (d, J=6.8 Hz,6H), 1.03 (t, J=7.6 Hz, 3H). LC-MS (m/z) 420.4 (MH⁺); t_(R)=0.59 (MethodD).

SUPPORTING EXAMPLE S951-isopropyl-5-(2-methoxy-3-pyridyl)-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-methoxypyridin-3-yl)boronic acid and(2-methoxypyridin-3-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.20-8.18 (m, 1H), 8.16-8.14 (m, 2H),7.64-7.62 (m, 1H), 7.04-7.03 (m, 1H), 6.97 (s, 1H), 6.93-6.92 (m, 1H),5.24-5.21 (m, 1H), 4.93-4.87 (m, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.04 (s,3H), 3.89 (s, 3H), 2.64 (s, 3H), 1.65 (d, J=6.4 Hz, 6H). LC-MS (m/z)419.1 (MH⁺); t_(R)=1.82 (Method A).

SUPPORTING EXAMPLE S961-isopropyl-5-(2-methoxy-3-pyridyl)-N-[(6-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-methoxypyridin-3-yl)boronic acid and (6-methoxy-3-pyridyl)methanamine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26 (d, J=1.6 Hz, 1H), 8.16-8.21 (m,2H), 7.67 (dd, J=2.4, 8.4 Hz, 1H), 7.02-7.07 (m, 2H), 6.80 (d, J=8.8 Hz,1H), 4.76-4.82 (m, 1H), 4.69 (brs, 1H), 4.47 (d, J=5.2 Hz, 2H), 3.96 (s,3H), 3.94 (s, 3H), 2.65 (s, 3H), 1.61 (d, J=6.4 Hz, 6H). LC-MS (m/z) 419(MH⁺); t_(R)=1.83 (Method A).

SUPPORTING EXAMPLE S975-(2-isopropoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-isopropoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-methyl-1H-pyrazole-4-carbaldehyde.

¹H NMR (600 MHz, DMSO) δ 8.21-8.09 (m, 2H), 7.58 (d, J=9.7 Hz, 1H), 7.38(s, 1H), 7.08 (s, 1H), 7.06 (dd, J=7.3, 4.9 Hz, 1H), 6.67 (t, J=5.5 Hz,1H), 5.44-5.33 (m, 1H), 5.16 (dt, J=12.7, 6.4 Hz, 1H), 4.36 (d, J=5.5Hz, 2H), 3.76 (s, 3H), 2.46 (s, 3H), 1.45 (d, J=6.4 Hz, 6H), 1.23 (d,J=6.2 Hz, 6H). LC-MS (m/z) 420.4 (MH⁺); t_(R)=0.52 (Method E).

SUPPORTING EXAMPLE S985-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.21-8.17 (m, 2H), 8.12 (s, 1H), 7.15(s, 1H), 7.02-6.99 (m, 1H), 5.60 (brs, 1H), 4.99-4.93 (m, 1H), 4.65 (s,2H), 4.46 (q, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.65 (d, J=6.4 Hz, 6H), 1.39(t, J=7.2 Hz, 3H). LC-MS (m/z) 393.1 (MH⁺); t_(R)=2.3 (Method C).

SUPPORTING EXAMPLE S995-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(2H-tetrazol-5-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2H-tetrazole-5-carbaldehyde.

¹H NMR (DMSO-d₆ 400 MHz): δ 8.17-8.13 (m, 2H), 7.09-7.05 (m, 1H), 6.99(s, 1H), 6.91 (br. s, 1H), 5.20-5.14 (m, 1H), 4.79 (d, J=5.2 Hz, 2H),4.30 (q, J=6.8 Hz, 2H), 2.47 (s, 3H), 1.49 (d, J=6.4 Hz, 6H), 1.22 (t,J=6.8 Hz, 3H). LC-MS (m/z) 394 (MH⁺); t_(R)=1.77 (Method C).

SUPPORTING EXAMPLE S1005-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand picolinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.66-8.64 (m, 1H), 8.26 (dd, J=2.0,7.2 Hz, 1H), 8.18 (dd, J=2.0, 4.8 Hz, 1H), 7.77-7.72 (m, 1H), 7.38-7.36(m, 1H), 7.30-7.28 (m, 1H),7.14 (s, 1H), 7.03 (dd, J=4.8, 7.2 Hz, 1H),6.53 (brs, 1H), 5.15-5.08 (m, 1H), 4.62 (d, J=4.0 Hz, 2H), 4.48 (q,J=6.8 Hz, 2H), 2.67 (s, 3H), 1.70 (d, J=6.8 Hz, 6H), 1.42 (t, J=7.2 Hz,3H). LC-MS (m/z) 403.1 (MH⁺); t_(R)=2.15 (Method A).

SUPPORTING EXAMPLE S1015-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(6-methyl-2-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-methylpicolinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.27-8.26 (m, 1H), 8.19-8.18 (m, 1H),7.66-7.62 (m, 1H), 7.18-7.14 (m, 2H), 7.11 (s, 1H), 7.04 (dd, J=4.8, 7.2Hz, 1H), 6.84 (brs, 1H), 5.22-5.19 (m, 1H), 4.57 (d, J=3.6 Hz, 2H), 4.49(q, J=6.8 Hz, 2H), 2.68 (s, 3H), 2.61 (s, 3H), 1.73 (d, J=6.4 Hz, 6H),1.43 (t, J=7.2 Hz, 3H). LC-MS (m/z) 417.1 (MH⁺); t_(R)=2.04 (Method A).

SUPPORTING EXAMPLE S1025-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-methoxypicolinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.28-8.26 (m, 1H), 8.19-8.18 (m, 1H),7.65-7.61 (m, 1H), 7.17 (s, 1H), 7.05-7.02 (m, 1H), 6.96-6.94 (m, 1H),6.75-6.72 (m, 1H), 6.17 (brs, 1H), 5.11-5.08 (m, 1H), 4.55-4.46 (m, 4H),4.01 (s, 3H), 2.67 (s, 3H), 1.66 (d, J=6.0 Hz, 6H), 1.43 (t, J=7.2 Hz,3H). LC-MS (m/z) 433.1 (MH⁺); t_(R)=2.47 (Method A).

SUPPORTING EXAMPLE S1035-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-4-pyridyl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-methylisonicotinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.50 (d, J=5.2 Hz, 1H), 8.22 (dd,J=2.0, 7.2 Hz, 1H), 8.15 (dd, J=2.0, 4.2 Hz, 1H), 7.20 (s, 1H), 7.15 (d,J=5.2 Hz, 1H), 7.03 (s, 1H), 7.00 (dd, J=5.2, 7.6 Hz, 1H), 4.91-4.86 (m,2H), 4.57 (d, J=5.2 Hz, 2H), 4.32 (q, J=7.2 Hz, 2H), 2.66 (s, 3H), 2.57(s, 3H), 1.67 (d, J=6.4 Hz, 6H), 1.21 (t, J=7.2 Hz, 3H). LC-MS (m/z)417.1 (MH⁺); t_(R)=1.53 (Method A).

SUPPORTING EXAMPLE S1045-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(2-methoxy-4-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-methoxyisonicotinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.22 (d, J=7.6 Hz, 1H), 8.18-8.14 (m,2H), 7.04 (s, 1H), 7 (dd, J=5.2, 7.6 Hz 1H), 6.92 (d, J=5.2 Hz 1H), 6.79(s, 1H), 4.89-4.86 (m, 2H), 4.56 (d, J=5.2 Hz, 2H), 4.34 (q, J=7.2 Hz,2H), 3.94 (s, 3H), 2.66 (s, 3H), 1.66 (d, J=6.8 Hz, 6H), 1.24 (t, J=7.2Hz, 3H). LC-MS (m/z) 433.1 (MH⁺); t_(R)=1.94 (Method A).

SUPPORTING EXAMPLE S1055-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-methylpyrimidine-4-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.65 (d, J=5.2 Hz, 1H), 8.26 (dd,J=2.0, 7.6 Hz, 1H), 8.18 (dd, J=2.0, 7.6 Hz, 1H), 7.20 (d, J=5.2 Hz,1H), 7.09 (s, 1H), 7.05-7.02 (m,1H), 6.45 (brs, 1H), 5.16-5.13 (m, 1H),4.59 (d, J=4.0 Hz, 2H), 4.46 (q, J=7.2 Hz, 2H), 2.81 (s, 3H), 2.67 (s,3H), 1.73 (d, J=6.4 Hz, 6H), 1.40 (t, J=7.2 Hz, 3H). LC-MS (m/z) 418.1(MH⁺); t_(R)=1.96 (Method C)

SUPPORTING EXAMPLE S1065-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-methoxynicotinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.24 (s, 1H), 8.19-8.18 (m, 1H),8.14-8.12 (m, 2H), 7.38 (s, 1H), 7.10-7.03 (m, 1H), 7.02-6.97 (m, 1H),6.94 (s, 1H), 5.27-5.21 (m, 1H), 4.58 (d, J=4.8 Hz, 2H),4.24 (q, J=7.2Hz, 2H), 3.78 (s, 3H), 2.46 (s, 3H), 1.48 (d, J=6.0 Hz, 6H), 1.10 (t,J=6.8 Hz, 3H). LC-MS (m/z) 433.1 (MH⁺); t_(R)=1.63 (Method A).

SUPPORTING EXAMPLE S1075-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[[6-(trifluoromethyl)-2-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-(trifluoromethyl)picolinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.27 (dd, J=2.0, 7.2 Hz, 1H), 8.18(dd, J=4.8, 2.0 Hz 1H), 8.00-7.95 (m, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.59(d, J=7.6 Hz ,1H), 7.13 (s, 1H), 7.04 (dd, J=7.2, 4.8 Hz, 1H), 6.68(brs, 1H), 5.19-5.16 (m, 1H), 4.70 (d, J=3.6 Hz, 2H), 4.49 (q, J=7.2 Hz,2H), 2.67 (s, 3H), 1.71 (d, J=6.4 Hz, 6H), 1.44 (t, J=7.2 Hz, 3H). LC-MS(m/z) 471 (MH⁺); t_(R)=2.34 (Method A).

SUPPORTING EXAMPLE S1083-[[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]amino]methyl]-1-methyl-pyridin-2-one

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.31-8.24 (m, 1H), 8.19-8.17 (m, 1H),7.50-7.42 (m, 1H), 7.30-7.28 (m, 1H), 7.15 (s, 1H), 7.05-7.02 (m, 1H),6.21-6.17 (m, 1H), 5.06-4.95 (m, 1H), 4.51-4.45 (m, 4H), 3.59 (s, 3H),2.65 (s, 3H), 1.64 (d, J=6.8 Hz, 6H), 1.40 (t, J=7.2 Hz, 3H). LC-MS(m/z) 433 (MH⁺); t_(R)=1.93 (Method C).

SUPPORTING EXAMPLE S1095-(2-ethoxy-3-pyridyl)-N-[(1-ethylpyrazol-4-yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-ethyl-1H-pyrazole-4-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.28 (dd, J=7.6, 2.0 Hz, 1H), 8.18(dd, J=4.8, 1.6 Hz, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 7.25 (s, 1H), 7.03(dd, J=7.6, 5.2 Hz, 1H), 4.77-4.50 (m, 1H), 4.52-4.45 (m, 3H), 4.39 (d,J=4.8 Hz, 2H), 4.2 (q, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.59 (d, J=6.8 Hz,6H), 1.52 (t, J=7.2 Hz, 3H), 1.40 (t, J=6.8 Hz, 3H). LC-MS (m/z) 420.1(MH⁺); t_(R)=2.13 (Method F).

SUPPORTING EXAMPLE S1105-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(1-propylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-propyl-1H-pyrazole-4-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.27 (dd, J=2.0, 7.2 Hz, 1H), 8.18(dd, J=2.0, 5.2 Hz, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 7.24 (s, 1H), 7.03(dd, J=4.8, 7.2 Hz, 1H), 4.77-4.74 (m, 1H), 4.48 (q, J=7.2 Hz, 3H), 4.39(d, J=4.4 Hz, 2H), 4.09 (t, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.94-1.88 (m,2H), 1.59 (d, J=6.4 Hz, 6H), 1.4 (t, J=6.8 Hz, 3H), 0.93 (t, J=7.2 Hz,3H). LC-MS (m/z) 434.1 (MH⁺); t_(R)=1.89 (Method A).

SUPPORTING EXAMPLE S1115-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-methoxynicotinaldehyde. ¹H NMR (Chloroform-d, 400 MHz): δ8.30-8.24 (m, 2H), 8.20-8.15 (m, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.21 (s,1H), 7.04-7.01 (m, 1H), 6.80 (d, J=8.0 Hz, 1H), 4.80 (dd, J=4.8, 6.4 Hz,1H), 4.65 (brs, 1H), 4.49-4.42 (m, 4H), 3.96 (s, 3H), 2.66 (s, 3H), 1.59(d, J=4.8 Hz, 6H), 1.40-1.34 (m, 3H). LC-MS (m/z) 433.1 (MH⁺);t_(R)=2.33 (Method F).

SUPPORTING EXAMPLE S1125-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-methoxypicolinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.33 (d, J=1.6 Hz, 1H), 8.26 (dd,J=2.0, 7.6 Hz, 1H), 8.18 (dd, J=2.0, 4.8 Hz, 1H), 7.31-7.28 (m, 2H),7.13 (s, 1H), 7.03 (dd, J=7.2, 7.6 Hz, 1H), 6.36 (s, 1H), 5.11-5.05 (m,1H), 4.56 (d, J=4.4 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H), 3.91 (s, 3H), 2.66(s, 3H), 1.69 (d, J=7.2 Hz, 6H), 1.42 (t, J=7.2 Hz, 3H). LC-MS (m/z)433.1 (MH⁺); t_(R)=2.14 (Method A).

SUPPORTING EXAMPLE S1135-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methylthiazol-4-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1,from 5,7-dibromo-3-methyl-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridine,(2-ethoxy-3-pyridyl)boronic acid and (2-methylthiazol-4-yl)methanamine.

¹H NMR (Chloroform-d, 400 MHz) δ 8.26 (dd, J=1.6, 7.2 Hz 1H), 8.18 (dd,J=2.0, 4.8 Hz 1H), 7.24 (s, 1H), 7.05-7.02 (m, 2H), 5.94-5.85 (m, 2H),5.28-5.25 (m, 2H), 5.20-5.16 (m, 2H), 4.57 (d, J=5.2 Hz, 2H), 4.46 (q,J=7.2 Hz, 2H), 2.76 (s, 3H), 2.66 (s, 3H), 1.39 (t, J=7.2 Hz, 3H). LC-MS(m/z) 437.4 (MH⁺); t_(R)=0.46 minutes (Method E).

SUPPORTING EXAMPLE S1145-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxypyrazin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-methoxypyrazine-2-carbaldehyde.

¹H NMR (400 MHz, Chloroform-d,): δ 8.24-8.28 (m, 2H), 8.16-8.23 (m, 2H),7.18 (s, 1H), 7.04 (brt, J=5.84 Hz, 1H), 5.80 (brs, 1H), 4.93-5.06 (m,1H), 4.60 (brd, J=3.75 Hz, 2H), 4.48 (q, J=6.69 Hz, 2H), 4.00 (s, 3H),2.66 (s, 3H), 1.66 (brd, J=6.39 Hz, 6H), 1.41 (t, J=6.95 Hz, 3H). LC-MS(m/z) 434.1 (MH⁺); t_(R)=1.99 (Method A).

SUPPORTING EXAMPLE S1155-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(3-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand nicotinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ=8.73 (s, 1H), 8.61 (d, J=3.6 Hz, 1H),8.24 (d, J=6.0 Hz, 1H), 8.16 (dd, J=1.6, 4.4 Hz, 1H), 7.76 (d, J=8.4 Hz,1H), 7.36-7.33 (m, 1H), 7.18 (s, 1H), 7.01 (dd, J=4.8, 7.6 Hz, 1H), 4.82(s, 1H), 4.75 (s, 1H), 4.60 (d, J=5.2 Hz, 2H), 4.40 (q, J=6.8 Hz, 2H),2.65 (s, 3H), 1.62 (d, J=6.4 Hz, 6H), 1.30 (t, J=7.2 Hz, 3H). LC-MS(m/z) 403.1 (MH⁺); t_(R)=1.41 (Method A).

SUPPORTING EXAMPLE S1165-(2-ethoxy-3-pyridyl)-N-[(6-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-fluoronicotinaldehyde.

¹H NMR (Cloroform-d, 400 MHz): δ 8.33 (s, 1H), 8.26-8.24 (m, 1H),8.18-8.17 (m, 1H), 7.88-7.86 (m, 1H), 7.17 (s, 1H), 7.04-6.98 (m, 2H),4.83-4.82 (m, 1H), 4.74-4.72 (m, 1H), 4.59-4.58 (m, 2H), 4.41 (q, J=6.8Hz, 2H), 2.66 (s, 3H), 1.63 (d, J=6.8 Hz, 6H), 1.31 (t, J=6.8 Hz, 3H).LC-MS (m/z) 421 (MH⁺); t_(R)=1.89 (Method A).

SUPPORTING EXAMPLE S117N-[[6-(difluoromethyl)-3-pyridyl]methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 6-(difluoromethyl)nicotinaldehyde.

¹H NMR (Cloroform-d, 400 MHz): δ 8.76 (s, 1H), 8.24 (dd, J=7.2, 2.0 Hz,1H), 8.16 (dd, J=5.2, 2.0 Hz, 1H), 7.92 (d, J=8.0, 1H), 7.68 (d, J=8.2Hz, 1H), 7.13 (s, 1H), 7.01 (dd, J=7.2, 4.8 Hz, 1H), 6.67 (t, J=55.2 Hz,1H), 4.87-4.83 (m, 2H), 4.68 (d, J=5.2 Hz, 2H), 4.35 (q, J=6.8 Hz, 2H),2.66 (s, 3H), 1.65 (d, J=6.8 Hz, 6H), 1.24 (t, J=7.2 Hz, 3H). LC-MS(m/z) 453.1 (MH⁺); t_(R)=1.92 (Method A).

SUPPORTING EXAMPLE S1185-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methoxy-2-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 3-methoxypicolinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.33 (dd, J=2.0, 7.2 Hz, 1H), 8.23(dd, J=1.2, 4.8 Hz, 1H), 8.19 (dd, J=2.0, 5.2 Hz, 1H), 7.28-7.30 (m,2H), 7.22-7.24 (m, 1H), 7.04 (dd, J=4.8, 7.2 Hz, 1H), 6.96 (brs, 1H),5.12-5.21 (m, 1H), 4.57 (d, J=4.0 Hz, 2H), 4.52 (q, J=6.8 Hz, 2H), 3.94(s, 3H), 2.68 (s, 3H), 1.72 (d, J=6.4 Hz, 6H), 1.51 (t, J=7.0 Hz, 3H).LC-MS (m/z) 433.1 (MH⁺); t_(R)=2.08 (Method A).

SUPPORTING EXAMPLE S1195-(2-ethoxy-3-pyridyl)-3-methyl-141-methylpropyl]-N-(1H-pyrazol-3-ylmethyppyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 and 1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26 (dd, J=2.0, 7.6 Hz, 1H), 8.18(dd, J=2.0, 4.2 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.22 (s, 1H), 7.03 (dd,J=4.8, 7.2 Hz, 1H), 6.36 (d, J=2.4 Hz, 1H), 5.29 (br. s, 1H), 4.64-4.60(m, 1H), 4.57 (d, J=4.8 Hz, 2H), 4.48 (q, J=6.8 Hz, 2H), 2.66 (s, 3H),2.22-2.14 (m, 1H), 1.90-1.85 (m, 1H), 1.61(d, J=6.4 Hz, 3H), 1.43 (t,J=6.8 Hz, 3H), 0.89 (t, J=7.6 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺);t_(R)=2.25 (Method A).

SUPPORTING EXAMPLE S1205-(2-ethoxy-3-pyridyl)-3-methyl-141-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26 (dd, J=2.0, 7.2 Hz, 1H), 8.18(dd, J=2.0, 4.2 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.22 (s, 1H), 7.03 (dd,J=4.8, 7.2 Hz, 1H), 6.36 (d, J=2.4 Hz, 1H), 5.28 (br. s, 1H), 4.64-4.60(m, 1H), 4.57 (d, J=4.8 Hz, 2H), 4.48 (q, J=6.8 Hz, 2H), 2.66 (s, 3H),2.22-2.14 (m, 1H), 1.92-1.86 (m, 1H), 1.62 (d, J=6.8 Hz, 3H), 1.43 (t,J=6.8 Hz, 3H), 0.89 (t, J=7.2 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺);t_(R)=2.22 (Method A).

SUPPORTING EXAMPLE S1215-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 and 1-methyl-1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Cloroform-d, 400 MHz): δ 8.27 (dd, J=2.0, 7.2 Hz, 1H), 8.18 (dd,J=2.0, 5.2 Hz, 1H), 8.05 (s, 1H), 7.20 (s, 1H), 7.03 (dd, J=4.8, 7.2 Hz,1H), 5.49 (br. s, 1H), 4.69-4.65 (m, 1H), 4.57 (d, J=4.8 Hz, 2H), 4.49(q, J=6.8 Hz, 2H), 3.95 (s, 3H), 2.66 (s, 3H), 2.21-2.16 (m, 1H),1.94-1.91 (m, 1H), 1.64 (d, J=6.4 Hz, 3H), 1.45 (t, J=7.2 Hz, 3H), 0.93(t, J=7.2 Hz, 3H). LC-MS (m/z) 421.1 (MH⁺); t_(R)=2.26 (Method C).

SUPPORTING EXAMPLE S1225-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1-methyl-1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26 (dd, J=2.0, 7.2 Hz, 1H), 8.18(dd, J=2.0, 5.2 Hz, 1H), 8.05 (s, 1H), 7.21 (s, 1H), 7.03 (dd, J=4.8,7.2 Hz, 1H), 5.49 (br. s, 1H), 4.68-4.65 (m, 1H), 4.57 (d, J=4.8 Hz,2H), 4.49 (q, J=6.8 Hz, 2H), 3.95 (s, 3H), 2.65 (s, 3H), 2.21-2.16 (m,1H), 1.94-1.89 (m, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.45 (t, J=6.8 Hz, 3H),0.93 (t, J=7.6 Hz, 3H). LC-MS (m/z) 421.1 (MH⁺); t_(R)=2.29 (Method C).

SUPPORTING EXAMPLE S1235-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 and 5-methyl-1,3,4-oxadiazole-2-carbaldehyde.

¹H NMR (Cloroform-d, 400 MHz): δ 8.30-8.28 (m, 1H), 8.21-8.20 (m, 1H),7.25 (s, 1H), 7.06-7.01 (m, 1H), 5.28-5.20 (m, 1H), 4.76-4.64 (m, 3H),4.51 (q, J=7.2 Hz, 2H), 2.66 (s, 3H), 2.58 (s, 3H), 2.23-2.18 (m, 1H),1.94-1.91 (m, 1H), 1.65 (d, J=6.4 Hz, 3H), 1.45 (t, J=6.8 Hz, 3H), 0.91(t, J=7.2 Hz, 3H). LC-MS (m/z) 422.1 (MH⁺); t_(R)=2.22 (Method C).

SUPPORTING EXAMPLE S1245-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 5-methyl-1,3,4-oxadiazole-2-carbaldehyde.

¹H NMR (Cloroform-d, 400 MHz): δ 8.30-8.28 (m, 1H), 8.20-8.19 (m, 1H),7.25 (s, 1H), 7.06-7.02 (m, 1H), 5.20-5.18 (m, 1H), 4.73-4.71 (m, 2H),4.63-4.61 (m, 1H), 4.51 (q, J=7.2 Hz, 2H), 2.66 (s, 3H), 2.58 (s, 3H),2.23-2.16 (m, 1H), 1.94-1.90 (m, 1H), 1.65 (d, J=6.4 Hz, 3H), 1.44 (t,J=6.8 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H). LC-MS (m/z) 422.1 (MH⁺);t_(R)=2.17 (Method C).

SUPPORTING EXAMPLE S1255-(2-ethoxy-3-pyridyl)-N-[(5-methoxy-3-pyridyl)methyl]-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 5-methoxynicotinaldehyde.

¹H NMR (DMSO-d₆ 400 MHz): δ =8.21 (s, 1H), 8.16 (d, J=2.8 Hz, 1H), 8.13(s, 1H), 8.12-8.09 (m, 1H), 7.33-7.32 (m, 1H), 7.05-7.02 (m, 1H), 6.93(s, 1H), 6.91 (s, 1H), 4.96-4.93 (m, 1H), 4.57-4.56 (m, 2H), 4.25-4.20(m, 2H), 3.75 (s, 3H), 2.44 (s, 3H), 1.98-1.74 (m, 2H), 1.48 (d, J=6.4Hz, 3H), 1.08 (t, J=7.0 Hz, 3H), 0.73 (t, J=7.6 Hz, 3H). LC-MS (m/z)447.1 (MH⁺); t_(R)=1.62 (Method A).

SUPPORTING EXAMPLE S1265-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 2-methoxyisonicotinaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ=8.24 (dd, J=2.0, 7.6 Hz, 1H),8.17 (d,J=5.6 Hz, 1H), 8.15 (dd, J=1.6, 4.8 Hz, 1H), 7.07 (s, 1H), 7.00 (dd,J=5.2, 7.6 Hz, 1H), 6.91 (d, J=4.0 Hz, 1H), 6.78 (s, 1H), 4.80 (brs,1H), 4.55 (d, J=5.6 Hz, 3H), 4.35 (q, J=6.8 Hz, 2H), 3.94 (s, 3H), 2.66(s, 3H), 2.26-2.15 (m, 1H), 1.95-1.85 (m, 1H), 1.64 (d, J=6.4 Hz, 3H),1.25 (t, J=6.8 Hz, 3H), 0.90 (t, J=7.6 Hz, 3H). LC-MS (m/z) 447.1 (MH⁺);t_(R)=1.96 (Method A).

SUPPORTING EXAMPLE S1275-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(2-methyltetrazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 2-methyl-2H-tetrazole-5-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.28 (dd, J=7.6, 2.0 Hz, 1H), 8.18(dd, J=5.2, 2.0 Hz, 1H), 7.27 (s, 1H), 7.05-7.02 (m, 1H), 5.31-5.28 (m,1H), 4.79 (d, J=5.2 Hz, 2H), 4.67-4.62 (m, 1H), 4.50 (q, J=6.8 Hz, 2H),4.39 (s, 3H), 2.67 (s, 3H), 2.24-2.17 (m, 1H), 1.95-1.88 (m, 1H), 1.65(d, J=6.8 Hz, 3H), 1.45 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H). LC-MS(m/z) 422.1 (MH⁺); t_(R)=2.03 (Method C).

SUPPORTING EXAMPLE S1285-(2-ethoxy-3-pyridyl)-3-methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 5-methyl-1,2,4-oxadiazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26 (dd, J=2.0, 7.2 Hz, 1H), 8.18(dd, J=2.0, 4.2 Hz, 1H), 7.24 (s, 1H), 7.03 (dd, J=4.4, 7.2 Hz, 1H),5.17 (br. s, 1H), 4.65-4.60 (m, 3H), 4.50 (q, J=7.2 Hz, 2H), 2.65 (s,3H), 2.64 (s, 3H), 2.23-2.16 (m, 1H), 1.93-1.90 (m, 1H), 1.64 (d, J=6.4Hz, 3H), 1.44 (t, J=6.8 Hz, 3H), 0.92 (t, J=7.6 Hz, 3H). LC-MS (m/z)422.1 (MH⁺); t_(R)=2.05 (Method C).

SUPPORTING EXAMPLE S1295-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methyloxazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 2-methyloxazole-4-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ=8.27 (dd, J=2.0, 7.2 Hz, 1H), 8.18(dd, J=2.0, 5.2 Hz, 1H), 7.54 (s, 1H), 7.18 (s, 1H), 7.03 (dd, J=4.8,7.2 Hz, 1H), 5.11-4.91 (m, 1H), 4.61-4.55 (m, 1H), 4.48 (q,J=7.2 Hz,2H), 4.40 (d, J=4.8 Hz, 2H), 2.65 (s, 3H), 2.49 (s, 3H), 2.21-2.14 (m,1H), 1.92-1.85 (m, 1H), 1.63 (s, 3H), 1.40 (t, J=7.2 Hz, 3H), 0.89 (t,J=7.2 Hz, 3H). LC-MS (m/z) 421.1 (MH⁺); t_(R)=1.9 (Method A).

SUPPORTING EXAMPLE S1305-(2-ethoxy-3-pyridyl)-N-(1H-imidazol-4-ylmethyl)-3-methyl-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1H-imidazole-4-carbaldehyde.

¹H NMR (Cloroform-d, 400 MHz): δ=8.25 (dd, J=2.0, 7.2 Hz, 1H), 8.17 (dd,J=2.0, 4.8 Hz, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.21 (s, 1H), 7.03 (s, 1H),7.02-7.00 (m, 1H), 5.57-5.08 (m, 1H), 4.63-4.60 (m, 1H), 4.50-4.51 (m,4H), 2.64 (s, 3H), 2.18-2.12 (m, 1H), 1.90-1.85 (m, 1H), 1.61 (d, J=6.4Hz, 3H), 1.41 (t, J=7.2 Hz, 3H), 0.87 (t, J=7.2 Hz, 3H). LC-MS (m/z)406.1 (MH⁺); t_(R)=1.35 (Method A).

SUPPORTING EXAMPLE S1315-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 5-methyl-1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ=8.27 (dd, J=2.0, 7.2 Hz, 1H), 8.18(dd, J=2.0, 4.8 Hz, 1H), 7.20 (s, 1H), 7.04-7.01 (m, 1H), 6.08 (s, 1H),5.28 (brs, 1H), 4.61-4.58 (m, 1H), 4.51-4.46 (m, 4H), 2.65 (s, 3H), 2.35(s, 3H), 2.21-2.14 (m, 1H), 1.91-1.85 (m, 1H), 1.62 (d, J=6.8 Hz, 3H),1.43 (t, J=6.8 Hz, 3H), 0.89 (t, J=7.6 Hz, 3H). LC-MS (m/z) 420.1 (MH⁺);t_(R)=1.85 (Method A).

SUPPORTING EXAMPLE S1325-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methylimidazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1-methyl-1H-imidazole-4-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ=8.28 (dd, J=2.0, 7.6 Hz, 1H), 8.17(dd, J=2.0, 4.8 Hz, 1H), 7.45 (s, 1H), 7.20 (s, 1H), 7.04-7.01 (m, 1H),6.88 (s, 1H), 5.25 (brs, 1H), 4.61-4.58 (m, 1H), 4.48 (q, J=6.8 Hz, 2H),4.42 (d, J=4.8 Hz, 2H), 3.70 (s, 3H), 2.65 (s, 3H), 2.18-2.13 (m, 1H),1.89-1.85 (m, 1H), 1.60 (d, J=6.8 Hz, 3H), 1.42 (t, J=6.8 Hz, 3H), 0.88(t, J=7.2 Hz, 3H). LC-MS (m/z) 420.1 (MH⁺); t_(R)=1.38 (Method A).

SUPPORTING EXAMPLE S1335-(2-ethoxy-3-pyridyl)-3-methyl-N-[(2-methyloxazol-5-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 2-methyloxazole-5-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ=8.27 (dd, J=2.0, 7.6 Hz, 1H), 8.18(dd, J=2.0, 4.8 Hz, 1H), 7.25 (s, 1H), 7.03 (dd, J=4.8, 7.6 Hz, 1H),6.94 (s, 1H), 4.62 (brd, J=4.8 Hz, 1H), 4.55-4.46 (m, 5H), 2.65 (s, 3H),2.47 (s, 3H), 2.21-2.13 (m, 1H), 1.91-1.84 (m, 1H), 1.62 (d, J=6.8 Hz,3H), 1.41 (t, J=6.8 Hz, 3H), 0.87 (t, J=7.6 Hz, 3H). LC-MS (m/z) 421.1(MH⁺); t_(R)=1.81 (Method A).

SUPPORTING EXAMPLE S1343-methyl-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1-methyl-1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.27-8.25 (m, 1H), 8.19-8.17 (m, 1H),8.06 (s, 1H), 7.19 (s, 1H), 7.04-7.01 (m, 1H), 5.50-5.48 (m, 1H),4.71-4.66 (m, 1H), 4.56 (d, J=2.2 Hz, 2H), 4.39 (t, J=6.8 Hz, 2H), 3.96(s, 3H), 2.66 (s, 3H), 2.24-2.18 (m, 1H), 1.91-1.83 (m, 3H), 1.65 (d,J=3.2 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H). LC-MS(m/z) 435.1 (MH⁺); t_(R)=2.05 (Method C).

SUPPORTING EXAMPLE S1353-methyl-1-[1-methylpropyl]-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 12.66 (s, 1H), 8.16-8.11 (m, 2H), 7.57(s, 1H), 7.10-7.06 (m, 2H), 6.71 (t, J=6.0 Hz, 1H), 6.15-6.14 (m, 1H),4.93-4.91 (m, 1H), 4.50 (d, J=5.6 Hz, 2H), 4.26 (t, J=6.8 Hz, 2H), 2.45(s, 3H), 2.00-1.92 (m, 1H), 1.76-1.67 (m, 3H), 1.47 (d, J=6.4 Hz, 3H),0.94 (t, J=7.2 Hz, 3H), 0.73 (t, J=7.2 Hz, 3H). LC-MS (m/z) 420.1 (MH⁺);t_(R)=2.1 (Method C).

SUPPORTING EXAMPLE S1365-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 and 1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.24-8.19 (m, 3H), 7.62 (d, J=2.0 Hz,1H), 7.23 (s, 1H), 7.04-7.01 (m, 1H), 6.37 (d, J=2.4 Hz, 1H), 5.45 (s,1H), 4.71-4.67 (m, 1H), 4.59 (d, J=4.8 Hz, 2H), 4.49 (q, J=6.8 Hz, 2H),2.25-2.18 (m, 1H), 1.94-1.90 (m, 1H), 1.66 (d, J=6.4 Hz, 3H), 1.44 (t,J=7.2 Hz, 3H), 0.9 (t, J=7.2 Hz, 3H). SFC: t_(R)=4.729 min, ee %=97.49%.LC-MS (m/z) 392 (MH⁺); t_(R)=2.23 (Method A).

SUPPORTING EXAMPLE S1375-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.24-8.18 (m, 3H), 7.61 (d, J=2.4 Hz,1H), 7.23 (s, 1H), 7.04-7.01 (m, 1H), 6.37 (d, J=2.4 Hz, 1H), 5.44 (s,1H), 4.71-4.67 (m, 1H), 4.59 (d, J=4.8 Hz, 2H), 4.49 (q, J=6.8 Hz, 2H),2.25-2.18 (m, 1H), 1.96-1.90 (m, 1H), 1.66 (d, J=6.8 Hz, 3H), 1.43 (t,J=7.2 Hz, 3H), 0.9 (t, J=7.2 Hz, 3H). SFC: t_(R)=4.453 min, ee %=94.84%.LC-MS (m/z) 392.1 (MH⁺); t_(R)=2.23 (Method A).

SUPPORTING EXAMPLE S1385-(2-ethoxy-3-pyridyl)-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 and 5-methyl-1,3,4-oxadiazole-2-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.24-8.20 (m, 3H), 7.25 (s, 1H), 7.03(dd, J=4.8, 7.2 Hz, 1H), 5.37 (brs, 1H), 4.73-4.69 (m, 3H), 4.51 (q,J=7.2 Hz, 2H), 2.58 (s, 3H), 2.27-2.19 (m, 1H), 1.97-1.93 (m, 1H), 1.68(d, J=6.4 Hz, 3H), 1.44 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H).SFC-MS: t_(R)=4.24 min, ee %=98.70%. LC-MS (m/z) 408 (MH⁺); t_(R)=2.4(Method C).

SUPPORTING EXAMPLE S1395-(2-ethoxy-3-pyridyl)-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 5-methyl-1,3,4-oxadiazole-2-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.25-8.20 (m, 3H), 7.25 (s, 1H), 7.03(dd, J=4.8, 7.2 Hz, 1H), 5.31 (brs, 1H), 4.73-4.68 (m, 3H), 4.51 (q,J=7.2 Hz, 2H), 2.59 (s, 3H), 2.27-2.20 (m, 1H), 1.97-1.94 (m, 1H), 1.68(d, J=6.4 Hz, 3H), 1.45 (t, J=7.2 Hz, 3H), 0.92 (t, J=7.2 Hz, 3H).SFC-MS: t_(R)=3.997 min, ee %=97.68%. LC-MS (m/z) 408.1 (MH⁺); t_(R)=2.4(Method C).

SUPPORTING EXAMPLE S1405-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 1 and 1-methyl-1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.25-8.19 (m, 3H), 8.07 (s, 1H), 7.23(s, 1H), 7.03 (dd, J=4.8, 7.2 Hz, 1H), 5.61 (brs, 1H), 4.79-4.74 (m,1H), 4.59 (d, J=4.8 Hz, 2H), 4.50 (q, J=7.2 Hz, 2H), 3.96 (s, 3H),2.27-2.22 (m, 1H), 1.98-1.93 (m, 1H), 1.68 (d, J=6.8 Hz, 3H), 1.46 (t,J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H). SFC-MS: t_(R)=4.97 min, ee%=98.60%. LC-MS (m/z) 407 (MH⁺); t_(R)=2.44 (Method C).

SUPPORTING EXAMPLE S1415-(2-ethoxy-3-pyridyl)-1-[1-methylpropyl]-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and 1-methyl-1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.24-8.19 (m, 3H), 8.07 (s, 1H), 7.23(s, 1H), 7.03 (dd, J=4.8, 7.2 Hz, 1H), 5.60 (brs, 1H), 4.78-4.73 (m,1H), 4.59 (d, J=4.8 Hz, 2H), 4.50 (q, J=7.2 Hz, 2H), 3.96 (s, 3H),2.27-2.22 (m, 1H), 1.98-1.93 (m, 1H), 1.68 (d, J=6.8 Hz, 3H), 1.46 (t,J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H). SFC-MS: t_(R)=4.66 min, ee%=96.90%. LC-MS (m/z) 407.1 (MH⁺); t_(R)=2.44 (Method C).

SUPPORTING EXAMPLE S1421-isopropyl-3-methyl-N-[(1-methylimidazol-4-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from1-isopropyl-3-methyl-5-(2-propoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-methyl-1H-imidazole-4-carbaldehyde.

¹H NMR (Cloroform-d, 400 MHz): δ 8.28-8.26 (m, 1H), 8.20-8.18 (m, 1H),7.46 (s, 1H), 7.18 (s, 1H), 7.05-7.02 (m, 1H), 6.91 (s, 1H), 5.43 (brs,1H), 4.94-4.90 (m, 1H), 4.45-4.44 (m, 2H), 4.38 (t, J=6.8 Hz, 2H), 3.70(s, 3H), 2.65 (s, 3H), 1.87-1.78 (m, 2H), 1.62 (d, J=6.8 Hz, 6H), 1.05(t, J=7.6 Hz, 3H). LC-MS (m/z) 420.1 (MH⁺); t_(R)=1.75 (Method C).

SUPPORTING EXAMPLE S1431-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from1-isopropyl-3-methyl-5-(2-propoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 1H-pyrazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.25-8.23 (m, 1H), 8.19-8.17 (m, 1H),7.61 (d, J=1.2 Hz, 1H), 7.18 (s, 1H), 7.05-7.01 (m, 1H), 6.36 (d, J=1.2Hz, 1H), 5.40 (brs, 1H), 4.96-4.90 (m, 1H), 4.58 (d, J=2.4 Hz, 2H), 4.38(t, J=7.2 Hz, 2H), 2.65 (s, 3H), 1.86-1.82 (m, 2H), 1.64 (d, J=3.2 Hz,6H), 1.05 (t, J=7.6 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺); t_(R)=1.83 (MethodA).

SUPPORTING EXAMPLE S1445-(2-ethoxy-3-pyridyl)-3-methyl-1-[1-methylpropyl]-N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2

Prepared using the same procedure as described for supporting example29, from1-(sec-butyl)-5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine,enantiomer 2 and1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-3-carbaldehydefollowed by deprotection with TFA.

¹H NMR (Chloroform-d, 400 MHz): δ 11.58 (brs, 1H), 8.25 (d, J=2.0 Hz,1H), 8.23-8.17 (m, 2H), 7.19 (s, 1H), 7.01 (dd, J=4.8, 7.2 Hz, 1H), 5.51(brs, 1H), 4.69-4.66 (m, 3H), 4.48 (q, J=7.2 Hz, 2H), 2.66 (s, 3H),2.22-2.16 (m, 1H), 1.93-1.89 (m, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.42 (t,J=6.8 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H). LC-MS (m/z) 407.1 (MH⁺);t_(R)=1.91 (Method C) [α]_(D) ²⁰-3.40 (c=1.0, DCM).

SUPPORTING EXAMPLE S1451-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-5-(2-propoxy-3-pyridyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from1-isopropyl-3-methyl-5-(2-propoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ =8.26-8.23 (m, 1H), 8.19-8.17 (m, 1H),8.06 (s, 1H), 7.18 (s, 1H), 7.04-7.01 (m, 1H), 5.52-5.51 (m, 1H),5.01-4.95 (m, 1H), 4.57 (d, J=4.8 Hz, 2H), 4.38 (t, J=6.8 Hz, 2H), 3.95(s, 3H), 2.65 (s, 3H), 1.90-1.81 (m, 2H), 1.66 (d, J=6.4 Hz, 6H), 1.05(t, J=7.6 Hz, 3H). LC-MS (m/z) 421.1 (MH⁺); t_(R)=2.1 (Method B).

SUPPORTING EXAMPLE S1461-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)-N-(1H-1,2,4-triazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example29, from1-isopropyl-3-methyl-5-(2-propoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amineand1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-3-carbaldehydefollowed by deprotection with TFA.

¹H NMR (Chloroform-d, 400 MHz): δ 8.20-8.17 (m, 2H), 8.14 (s, 1H), 7.14(s, 1H), 7.03 (dd, J=4.2, 7.6 Hz, 1H), 5.59 (brs, 1H), 5.00-4.94 (m,1H), 4.64 (s, 2H), 4.36 (t, J=6.8 Hz, 2H), 2.65 (s, 3H), 1.85-1.76 (m,2H), 1.65 (d, J=6.8 Hz, 6H), 1.01 (t, J=7.2 Hz, 3H). LC-MS (m/z) 407.1(MH⁺); t_(R)=1.91 (Method C).

SUPPORTING EXAMPLE S1471-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-thiazol-2-yl-pyrazolo[4,3-b]pyridin-7-amine

To a solution of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(50 mg, 0.14 mmol) in DMF (2 mL) was added 2-(tributylstannyl)thiazole(103 mg, 0.28 mmol) and Pd(PPh₃)₄ (16 mg, 0.013 mmol). The mixture wasbubbled with N₂ and heated at 80° C. for 2 hours. The mixture was cooledto room temperature. ethyl acetate (20 mL) and water (10 mL) were added.The organic layer was washed with water (10 mL×2), brine (10 mL), driedover Na₂SO₄, filtered and concentrated. The crude was purified bypreparative TLC (SiO₂, ethyl acetate) to give1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(thiazol-2-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine(10 mg).

¹H NMR (Chloroform-d, 400 MHz): δ 7.88 (d, J=3.2 Hz, 1H), 7.58 (s,1H),7.46 (s, 2H), 7.40 (d, J=3.2 Hz, 1H), 4.75-4.68 (m, 1H), 4.54 (brs,1H), 4.46 (d, J=4.8 Hz, 2H), 3.94 (s, 3H), 2.65 (s, 3H), 1.58 (d, J=6.8Hz, 6H). LC-MS (m/z) 368 (MH⁺); t_(R)=1.91 (Method C).

SUPPORTING EXAMPLE S1481-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(5-methylthiazol-2-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example147, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-methyl-2-(tributylstannyl)thiazole.

¹H NMR (600 MHz, DMSO-d₆) δ 7.62 (s, 1H), 7.56 (s, 1H), 7.43 (s, 1H),7.20 (s, 1H), 6.86 (t, J=5.6 Hz, 1H), 5.16 (m,1H), 4.41 (d, J=5.5 Hz,2H), 3.77 (s, 3H), 2.47 (s, 3H), 2.45 (s, 3H), 1.44 (d, J=6.3 Hz, 6H).LC-MS (m/z) 382.3 (MH⁺); t_(R)=0.51 (Method D).

SUPPORTING EXAMPLE S1491-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(4-methylthiazol-2-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example147, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 4-methyl-2-(tributylstannyl)thiazole.

¹H NMR (500 MHz, Chloroform-d) δ 7.60 (s, 1H), 7.47 (s, 1H), 7.45 (s,1H), 6.96 (s, 1H), 4.73 (m, 1H), 4.53 (s, 1H), 4.49 (s, 2H), 3.96 (s,3H), 2.65 (s, 3H), 2.55 (s, 3H), 1.59 (d, J=6.4 Hz, 6H). LC-MS (m/z)382.4 (MH⁺); t_(R)=0.51 (Method D).

SUPPORTING EXAMPLE S1503-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-5-methyl-oxazolidin-2-one

A mixture of5-bromo-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine(20 mg, 0.06 mmol), 5-methyloxazolidin-2-one (7 mg, 0.07 mmol),Pd₂(dba)₃ (5 mg, 0.006 mmol), Xantphos (10 mg, 0.02 mmol), Cs₂CO₃ (25mg, 0.08 mmol) in dioxane (2 mL) was stirred at 85° C. for 12 hours. Themixture was concentrated to give a residue. The residue was purified bypreparative HPLC to give3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-5-methyl-oxazolidin-2-one(15 mg).

¹H NMR (Chloroform-d, 400 MHz): δ=7.59 (s, 1H), 7.55 (s, 2H), 4.80 (brd,J=6.8 Hz, 1H), 4.74-4.64 (m, 1H), 4.63-4.56 (m, 1H), 4.47 (dd, J=8.4,10.4 Hz, 1H), 4.39 (d, J=5.0 Hz, 2H), 3.98-3.93 (m, 1H), 3.92 (s, 3H),2.51 (s, 3H), 1.58 (s, 3H), 1.55 (d, J=6.3 Hz, 6H). LC-MS (m/z) 384.1(MH⁺); t_(R)=1.9 (Method C).

SUPPORTING EXAMPLE S1513-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]oxazolidin-2-one

Prepared using the same procedure as described for supporting example150, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand oxazolidin-2-one.

¹H NMR (600 MHz, DMSO-d₆) δ 7.65 (s, 1H), 7.45 (s, 1H), 7.41 (s, 1H),6.78 (t, J=5.7 Hz, 1H), 5.09 (m, 1H), 4.41 (m, 2H), 4.28 (d, J=5.6 Hz,2H), 4.19 (m, 2H), 3.77 (s, 3H), 2.36 (s, 3H), 1.40 (d, J=6.3 Hz, 6H).LC-MS (m/z) 370.2 (MH⁺); t_(R)=1.51 (Method J).

SUPPORTING EXAMPLE S1521-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]azetidin-2-one

Prepared using the same procedure as described for supporting example150, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand azetidin-2-one.

¹H NMR (600 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.45 (s, 1H), 6.94 (s, 1H),6.81 (t, J=5.6 Hz, 1H), 5.07 (m, 1H), 4.27 (d, J=5.5 Hz, 2H), 3.77 (s,3H), 3.66 (s, 2H), 3.04 (t, J=4.5 Hz, 2H), 2.35 (s, 3H), 1.40 (d, J=6.3Hz, 6H). LC-MS (m/z) 354.2 (MH⁺); t_(R)=1.46 (Method K).

SUPPORTING EXAMPLE S1531-rert-butyl-341-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]imidazolidin-2-one

Prepared using the same procedure as described for supporting example150, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-(tert-butyl)imidazolidin-2-one.

¹H NMR (500 MHz, Chloroform-d) δ 7.71 (s, 1H), 7.61 (s, 1H), 7.48 (s,1H), 6.52 (t, J=5.6 Hz, 1H), 5.10-4.94 (m, 1H), 4.25 (d, J=5.6 Hz, 2H),3.91-3.82 (m, 2H), 3.77 (s, 3H), 3.44 (t, J=7.9 Hz, 2H), 2.34 (s, 3H),1.48-1.23 (m, 15H). LC-MS (m/z) 425.2 (MH⁺); t_(R)=1.64 (Method K).

SUPPORTING EXAMPLE S1541-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]pyrrolidin-2-one

Prepared using the same procedure as described for supporting example150, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand pyrrolidin-2-one.

¹H NMR (600 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.67 (s, 1H), 7.47 (s, 1H),6.70 (t, J=5.7 Hz, 1H), 5.08 (m, 1H), 4.26 (d, J=5.6 Hz, 2H), 4.06-3.96(m, 2H), 3.77 (s, 3H), 2.56 (t, J=8.0 Hz, 2H), 2.36 (s, 3H), 2.06-1.94(m, 2H), 1.39 (d, J=6.3 Hz, 6H). LC-MS (m/z) 368.2 (MH⁺); t_(R)=1.39(Method K).

SUPPORTING EXAMPLE S1553-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-4-methyl-oxazolidin-2-one

Prepared using the same procedure as described for supporting example150, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 4-methyloxazolidin-2-one.

¹H NMR (Chloroform-d, 400 MHz): δ=7.55 (d, J=2.4 Hz, 2H), 7.45 (s, 1H),5.14-5.03 (m, 1H), 4.73-4.64 (m, 1H), 4.62-4.51 (m, 2H), 4.38 (dd,J=5.0, 9.6 Hz, 2H), 4.07 (dd, J=4.5, 8.3 Hz, 1H), 3.92 (s, 3H), 2.51 (s,3H), 1.56 (dd, J=1.7, 6.5 Hz, 6H), 1.52 (d, J=6.2 Hz, 3H). LC-MS (m/z)384.1 (MH⁺); t_(R)=2 (Method B).

SUPPORTING EXAMPLE S1564-ethyl-3-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]oxazolidin-2-one

Prepared using the same procedure as described for supporting example150, from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 4-ethyloxazolidin-2-one.

¹H NMR (Chloroform-d, 400 MHz):δ 7.55 (d, J=2.0 Hz, 2H), 7.46 (s, 1H),5.1-4.98 (m, 1H), 4.70-4.66 (m, 1H), 4.57-4.55 (m, 1H), 4.51 (t, J=8.8Hz, 1H), 4.40-4.36 (m, 2H), 4.21-4.18 (m, 1H), 3.92 (s, 3H), 2.50 (s,3H), 2.02-1.79 (m, 2H), 1.55 (d, J=4.8 Hz 6H), 0.93 (t, J=7.6 Hz, 3H).LC-MS (m/z) 398.1 (MH⁺); t_(R)=1.99 (Method C).

SUPPORTING EXAMPLE S157N4[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]methyl]-5-methoxy-pyridin-3-amine

A mixture ofN-[(5-bromo-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl)methyl]-5-methoxy-pyridin-3-amine(69 mg, 0.18 mmol), (2-ethoxy-3-pyridyl)boronic acid (59 mg, 0.35 mmol),Pd(dppf)Cl₂ (26 mg, 0.03 mmol), Cs₂CO₃ (115 mg, 0.35 mmol) in dioxane (3mL) and water (1 mL) was degassed and purged with N₂ 3 times, and thenthe mixture was stirred at 100° C. for 2 hours under a N₂ atmosphere.Water (20 mL) was added and the mixture was extracted with ethyl acetate(30 mL×3). The combined organic layers were washed with brine (20 mL),dried over Na₂SO₄ and concentrated. The crude mixture was purified bypreparative HPLC to give N-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]methyl]-5-methoxy-pyridin-3-amine (48.16mg).

¹H NMR (Cloroform-d, 400 MHz): δ 8.27 (dd, J=2.0, 7.6 Hz, 1H), 8.18 (dd,J=2.0, 4.8 Hz, 1H), 8.00 (s, 1H), 7.81-7.80 (m, 2H), 7.05-7.02 (m, 1H),6.49-6.48 (m, 1H), 4.90-4.87 (m, 1H), 4.74 (d, J=5.6 Hz, 2H), 4.40 (q,J=7.2 Hz, 2H), 4.18-4.16 (m, 1H), 3.83 (s, 3H), 2.72 (s, 3H), 1.58 (d,J=7.2 Hz, 6H).1.27 (t, J=7.2 Hz, 3H). LC-MS (m/z) 433.1 (MH⁺);t_(R)=1.88 (Method A).

SUPPORTING EXAMPLE S158N-[[5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl]methyl]-1-methyl-1,2,4-triazol-3-amine

Prepared using the same procedure as described for supporting example157, fromN-[(5-bromo-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-yl)methyl]-1-methyl-1,2,4-triazol-3-amineand (2-ethoxy-3-pyridyl)boronic acid.

¹H NMR (Cloroform-d, 400 MHz): δ 8.24 (dd, J=2.0, 7.6 Hz, 1H), 8.18 (dd,J=2.0, 5.2 Hz, 1H), 7.99 (s, 1H), 7.67 (s, 1H), 7.03 (dd, J=4.8, 7.2 Hz,1H), 5.01-4.98 (m, 1H), 4.91 (d, J=6.0 Hz, 2H), 4.56 (t, J=6.0 Hz, 1H),4.45 (q, J=7.2 Hz, 2H), 3.77 (s, 3H), 2.70 (s, 3H), 1.58 (d, J=6.4 Hz,6H), 1.34 (t, J=7.2 Hz, 3H). LC-MS (m/z) 407.1 (MH⁺); t_(R)=2.17 (MethodC).

SUPPORTING EXAMPLE S1595-(2-ethoxy-3-pyridyl)-1-isopropyl-742-(5-methoxy-3-pyridyl)ethyl]-3-methyl-pyrazolo[4,3-b]pyridine

A mixture of5-(2-ethoxypyridin-3-yl)-7-ethynyl-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine(0.05 g, 0.16 mmol), 3-iodo-5-methoxy-pyridine (37 mg, 0.16 mmol), CuI(3 mg, 0.016 mmol), Pd(dppf)Cl₂ (11 mg, 0.016 mmol) and Et₃N (79 mg,0.78 mmol) in dioxane (3 mL) was stirred at 100° C. under a N₂atmosphere for 4 hours. The mixture was worked up with 4 other batchs(each with same procedure and same amount of starting material). Themixture was concentrated and extracted with ethyl acetate (20 mL×2),dried over Na₂SO₄, and concentrated to give residue. The mixture waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=10/1 to 1/1) to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-7-((5-methoxypyridin-3-yl)ethynyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine(0.025 g). A mixture of5-(2-ethoxypyridin-3-yl)-1-isopropyl-7-((5-methoxypyridin-3-yl)ethynyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine(0.02 g, 0.047 mmol), Pd/C (0.005 g, 0.047 mmol, 10%), H₂ (15 psi) inethyl acetate (2 mL) was stirred at room temperature for 0.25 hour. Themixture was filtered and the filtrate was concentrated to give residue.The residue was purified by preparative HPLC to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-7-(2-(5-methoxypyridin-3-ypethyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine(7 mg).

¹H NMR (Chloroform-d, 400 MHz): δ=8.27-8.24 (m, 1H), 8.24-8.14 (m, 3H),7.79 (s, 1H), 7.05 (dd, J=4.8, 7.2 Hz, 1H), 6.96 (t, J=2.0 Hz, 1H),4.98-4.79 (m, 1H), 4.48 (q, J=7.2 Hz, 2H), 3.81 (s, 3H), 3.43-3.29 (m,2H), 3.18-3.01 (m, 2H), 2.70 (s, 3H), 1.59 (d, J=6.8 Hz, 6H), 1.41 (t,J=6.8 Hz, 3H). LC-MS (m/z) 432.1 (MH⁺); t_(R)=1.97 (Method A).

SUPPORTING EXAMPLE S1605-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-7-[2-(1-methyl-1,2,4-triazol-3-ypethyl]pyrazolo[4,3-b]pyridine

Prepared using the same procedure as described for supporting example159, from5-(2-ethoxypyridin-3-yl)-7-ethynyl-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridineand added 3-bromo-1-methyl-1H-1,2,4-triazole.

¹H NMR (Chloroform-d, 400 MHz): δ 8.23 (dd, J=2.0, 7.6 Hz, 1H), 8.19(dd, J=1.6, 4.4 Hz, 1H), 7.99 (s, 1H), 7.81 (s, 1H), 7.04 (dd, J=4.2,7.6 Hz, 1H), 5.11-5.04 (m, 1H), 4.48 (q, J=7.2 Hz, 2H), 3.90 (s, 3H),3.55-3.51 (m, 2H), 3.23-3.18 (m, 2H), 2.70 (s, 3H), 1.61 (d, J=6.8 Hz,6H), 1.43 (t, J=6.8 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺); t_(R)=2.3 (MethodC).

SUPPORTING EXAMPLE S1615-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amineand SUPPORTING EXAMPLE S1625-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Cs₂CO₃ (16.6 mg, 0.051 mmol) and iodomethane (510 μl, 0.051 mmol, 100mM, THF) were added toN-((4H-1,2,4-triazol-3-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(20 mg, 0.051 mmol) in THF (1.3 mL). The reaction mixture was stirred ina sealed vial at 80° C. for 50 minutes. The reaction mixture wasconcentrated in vacuo. Water was added. The mixture was extracted withethyl acetate. The organic phase was washed with brine, dried overMgSO4, filtered and concentrated in vacuo. The residue was purified bySFC to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(2 mg) and5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-N-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(1 mg)

SUPPORTING EXAMPLE S1615-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

¹H NMR (600 MHz, Chloroform-d) δ 8.28 (dt, J=7.3, 1.4 Hz, 1H), 8.19 (dd,J=4.9, 1.9 Hz, 1H), 7.92 (s, 1H), 7.17 (s, 1H), 7.05 (dd, J=7.3, 4.9 Hz,1H), 5.72 (s, 1H), 4.98 (hept, J=6.6 Hz, 1H), 4.56 (d, J=4.1 Hz, 2H),4.49 (q, J=7.0 Hz, 2H), 3.95 (s, 3H), 2.66 (s, 3H), 1.66 (d, J=6.5 Hz,6H), 1.44 (t, J=7.0 Hz, 3H). LC-MS (m/z) 407.4 (MH⁺); t_(R)=0.51 (MethodD).

SUPPORTING EXAMPLE S1625-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(4-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

¹H NMR (600 MHz, DMSO-d6) 6 8.43 (s, 1H), 8.19 (dd, J=4.9, 1.9 Hz, 1H),8.12 (dd, J=7.3, 2.0 Hz, 1H), 7.32 (s, 1H), 7.09 (dd, J=7.4, 4.8 Hz,1H), 6.80 (t, J=5.2 Hz, 1H), 5.17 (hept, J=6.8 Hz, 1H), 4.67 (d, J=5.0Hz, 2H), 4.42 (q, J=7.0 Hz, 2H), 3.71 (s, 3H), 2.46 (s, 3H), 1.45 (d,J=6.3 Hz, 6H), 1.36 (t, J=7.0 Hz, 3H). LC-MS (m/z) 407.4 (MH⁺);t_(R)=0.49 (Method D).

SUPPORTING EXAMPLE S1635-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine

A suspension of5-(2-ethoxypyridin-3-yl)-3-methyl-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(80 mg, 0.22 mmol, prepared using the same procedure as described forsupporting example 29, from5-(2-ethoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine and1-methyl-1,2,4-triazole-3-carbaldehyde), 3-iodooxetane (81 mg, 0.44mmol) and t-BuOK (215 mg, 1.91 mmol) in DMF (2 mL) was heated to 120° C.for 34 hours. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was purified by preparative HPLCtwice to give5-(2-ethoxy-3-pyridyl)-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine(8 mg).

¹H NMR (Cloroform-d, 400 MHz) δ 8.28 (dd, J=2.2, 7.4 Hz, 1H), 8.19 (dd,J=2.0, 4.8 Hz, 1H), 8.06 (s, 1H), 7.26 (s, 1H), 7.03 (dd, J=4.8, 7.4 Hz,1H), 5.97-5.93 (m, 1H), 5.34 (t, J=6.4 Hz, 2H), 5.19 (t, J=7.2 Hz, 2H),4.57 (d, J=5.2 Hz, 2H), 4.49 (q, J=6.8 Hz, 2H), 3.96 (s, 3H), 2.67 (s,3H), 1.44 (t, J=7.2 Hz, 3H). LC-MS (m/z) 421.1 (MH⁺); t_(R)=2.04 (MethodB).

SUPPORTING EXAMPLE S1645-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylsulfanyl]pyrazolo[4,3-b]pyridine

KO^(t)Bu (6.9 mg, 0.06 mmol) was added to a solution of 6-methylheptyl3-((5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thio)propanoate(21 mg, 0.04 mmol) in DMF (0.59 mL) at rt. The resulting mixture wasstirred at rt over 50 minutes after which4-(chloromethyl)-1-methyl-1H-pyrazole (13.4 mg, 0.06 mmol) was added inone portion. After stirring at rt over 6 hours the mixture was cooled toice bath temperature, quenched with a few drops of water and stirredwithout cooling bath for 5 minutes. Partitioned between ethyl acetate(40 mL) and water (2×15 mL). The org. layer was further washed withbrine (10 mL). The combined org. layers were dried (Na₂SO₄) andconcentrated. The crude material was purified by flash chromatographywith heptane:ethyl acetate 1:0 to 0:1 to give5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-7-(((1-methyl-1H-pyrazol-4-yl)methypthio)-1H-pyrazolo[4,3-b]pyridine(8 mg).

¹H NMR (DMSO-d₆ 600 MHz): δ 8.28-8.22 (m, 2H), 7.94 (s, 1H), 7.76 (s,1H), 7.47 (s, 1H), 7.16 (dd, J=7.3, 4.9 Hz, 1H), 5.33 (hept, J=6.5 Hz,1H), 4.44 (q, J=7.0 Hz, 2H), 4.39 (s, 2H), 3.79 (s, 3H), 2.54 (s, 3H),1.47 (d, J=6.5 Hz, 6H), 1.34 (t, J=7.0 Hz, 3H). LC-MS (m/z) 423.6 (MH⁺);t_(R)=0.76 (Method D).

SUPPORTING EXAMPLE S165N4[1-(difluoromethyppyrazol-4-yl]methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

To a solution ofN-((1-(difluoromethyl)-1H-pyrazol-4-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(15 mg, 0.027 mmol) in DCM (0.5 mL) was added trifluoro acetic acid (0.5mL). The mixture was stirred at room temperature for 1 hour. Water (3mL) was added and the mixture was poured into a saturated, aqueoussolution of NaHCO₃. The mixture was extracted with ethyl acetate (5mL×3). The combined organic layers were washed with brine (5 mL), driedover Na₂SO₄ and concentrated. The crude mixture was purified by flashchromatography with heptane:ethyl acetate=1:0 to 0:1 to giveN-((1-(difluoromethyl)-1H-pyrazol-4-yl)methyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(11 mg, 0.025 mmol, 93% yield).

¹H NMR (600 MHz, Chloroform-d) δ 8.26 (dd, J=7.4, 2.0 Hz, 1H), 8.17 (dd,J=4.9, 2.0 Hz, 1H), 7.84 (d, J=2.7 Hz, 1H), 7.20 (s, 1H), 7.17 (t,J=60.7 Hz, 1H), 7.02 (dd, J=7.3, 4.9 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H),5.24 (s, 1H), 4.91 (hept, J=6.6 Hz, 1H), 4.57 (d, J=4.8 Hz, 2H), 4.47(q, J=7.0 Hz, 2H), 2.65 (s, 3H), 1.65 (d, J=6.5 Hz, 6H), 1.40 (t, J=7.0Hz, 3H). LC-MS (m/z) 442.5 (MH⁺); t_(R)=0.60 minutes (Method D).

SUPPORTING EXAMPLE S1665-(2-ethoxypyridin-3-yl)-N-((5-(fluoromethypisoxazol-3-yl)methyl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example165, from5-(2-ethoxypyridin-3-yl)-N-((5-(fluoromethypisoxazol-3-yl)methyl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

¹H NMR (600 MHz, Chloroform-d) δ 8.27 (dd, J=7.4, 2.0 Hz, 1H), 8.18 (dd,J=4.9, 2.0 Hz, 1H), 7.22 (s, 1H), 7.02 (dd, J=7.4, 4.9 Hz, 1H), 6.47 (d,J=2.6 Hz, 1H), 5.43 (d, J=47.3 Hz, 2H), 5.22 (s, 1H), 4.89 (hept, J=6.6Hz, 1H), 4.65 (d, J=5.2 Hz, 2H), 4.47 (q, J=7.0 Hz, 2H), 2.64 (s, 3H),1.64 (d, J=6.5 Hz, 6H), 1.39 (t, J=7.0 Hz, 3H). LC-MS (m/z) 425.6 (MH⁺);t_(R)=0.57 minutes (Method D).

SUPPORTING EXAMPLE S1675-(2-ethoxypyridin-3-yl)-N-((3-(fluoromethypisoxazol-5-yl)methyl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example165, from5-(2-ethoxypyridin-3-yl)-N-((3-(fluoromethypisoxazol-5-yl)methyl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

¹H NMR (600 MHz, Chloroform-d) δ 8.28 (dd, J=7.4, 2.0 Hz, 1H), 8.17 (dd,J=4.9, 2.0 Hz, 1H), 7.22 (s, 1H), 7.02 (dd, J=7.4, 4.9 Hz, 1H), 6.41 (s,1H), 5.44 (d, J=46.9 Hz, 2H), 4.90 (t, J=5.9 Hz, 1H), 4.84 (hept, J=6.6Hz, 1H), 4.73 (d, J=5.8 Hz, 2H), 4.45 (q, J=7.0 Hz, 2H), 2.65 (s, 3H),1.64 (d, J=6.5 Hz, 6H), 1.35 (t, J=7.0 Hz, 3H). LC-MS (m/z) 425.6 (MH⁺);t_(R)=0.55 minutes (Method D).

SUPPORTING EXAMPLE S1681-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-oxazol-2-yl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example147 from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand tributyl(oxazol-2-yl)stannane.

¹H NMR (Chloroform-d, 400 MHz): δ 7.83 (s, 1H), 7.59 (s, 1H), 7.46 (s,1H), 7.39 (s, 1H), 7.29 (s, 1H), 4.76-4.70 (m, 1H), 4.58 (brs, 1H), 4.44(d, J=4.2 Hz, 2H), 3.94 (s, 3H), 2.69 (s, 3H), 1.59 (d, J=6.4 Hz, 6H).LC-MS (m/z) 352 (MH⁺); t_(R)=1.75 minutes (Method C).

SUPPORTING EXAMPLE S1691-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(3-methyltriazol-4-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example147 from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-methyl-5-(tributylstannyl)-1H-1,2,3-triazole.

¹H NMR (Chloroform-d, 400 MHz): δ 7.93 (s, 1H), 7.57 (s, 1H), 7.45 (s,1H), 6.70 (s, 1H), 4.76-4.69 (m, 1H), 4.65 (brs, 1H), 4.48 (s, 3H), 4.39(d, J=4.4 Hz, 2H), 3.95 (s, 3H), 2.62 (s, 3H), 1.60 (d, J=6.4 Hz, 6H).LC-MS (m/z) 366 (MH⁺); t_(R)=1.69 minutes (Method C).

SUPPORTING EXAMPLE S1701-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl-N-[[2-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from [2-(trifluoromethyl)-3-pyridyl]methanamine,(2-methoxypyridin-3-yl)boronic acid and5,7-dichloro-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.67 (d, J=4.0 Hz 1H), 8.20 (dd,J=1.2, 7.2 Hz 1H), 8.15 (dd, J=2.0, 4.8 Hz 1H), 7.99 (d, J=7.6 Hz 1H),7.50 (dd, J=4.8, 8.0 Hz 1H), 7.01 (dd, J=5.2, 7.6 Hz 1H), 6.90 (s, 1H),5.07 (brs, 1H), 4.86-4.89 (m, 3H), 3.74 (s, 3H), 2.65 (s, 3H), 1.66 (d,J=6.8 Hz, 6H). LC-MS (m/z) 457 (MH⁺); t_(R)=1.89 minutes (Method A).

SUPPORTING EXAMPLE S1713-[1-isopropyl-7-[(2-methoxy-3-pyridyl)methylamino]-3-methyl-pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one

Prepared using the same procedure as described for supporting example 1from 5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-methoxypyridin-3-yl)methanamine and(2-oxo-1,2-dihydropyridin-3-yl)boronic acid.

¹H NMR (DMSO-d₆, 400 MHz): δ 11.73 (brs, 1H), 8.27 (dd, J=2.0, 7.2 Hz,1H), 8.01 (d, J=3.6 Hz, 1H), 7.57 (d, J=6.4 Hz, 1H), 7.45-7.35 (m, 1H),6.88 (dd, J=4.2, 7.2 Hz, 1H), 6.75-6.67 (m, 1H), 6.35-6.25 (m, 1H),5.20-5.14 (m, 1H), 4.45-4.40 (m, 2H), 3.91 (s, 3H), 2.43 (s, 3H), 1.43(d, J=6.4 Hz, 6H). LC-MS (m/z) 405 (MH⁺); t_(R)=1.95 minutes (Method C).

SUPPORTING EXAMPLE S1725-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(3-methoxy-4-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from 5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(3-methoxy-4-pyridyl)methanamine and (2-ethoxy-3-pyridyl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.32 (s, 1H), 8.26 (d, J=4.8 Hz, 1H),8.22 (d, J=7.2 Hz, 1H), 8.14 (d, J=4.2 Hz, 1H), 7.30-7.25 (m, 1H), 7.08(s, 1H), 7.01 (dd, J=4.8, 7.2 Hz, 1H), 5.02 (brs, 1H), 4.91-4.88 (m,1H), 4.58 (d, J=5.6 Hz, 2H), 4.35 (q, J=7.2 Hz, 2H), 4.01 (s, 3H), 2.65(s, 3H), 1.66 (d, J=7.2 Hz, 6H), 1.26 (t, J=7.2 Hz, 3H). LC-MS (m/z)433.1 (MH⁺); t_(R)=1.47 minutes (Method A).

SUPPORTING EXAMPLE S1731-isopropyl-5-(2-methoxy-3-pyridyl)-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 29from1-isopropyl-5-(2-methoxypyridin-3-yl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-methylthiazole-5-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.20-8.18 (m, 2H), 7.64 (s, 1H), 7.12(s, 1H), 7.07-7.04 (m, 1H), 4.88-4.77 (m, 2H), 4.77-4.68 (m, 2H), 4.00(s, 3H), 2.72 (s, 3H), 2.65 (s, 3H), 1.62 (d, J=6.8 Hz, 6H). LC-MS (m/z)409 (MH⁺); t_(R)=1.66 minutes (Method A).

SUPPORTING EXAMPLE S1745-(2-cyclopropoxypyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from 5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-methoxypyridin-3-yl)methanamine and2-cyclopropoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

¹H NMR (Chloroform-d, 600 MHz) δ 8.23 (dd, J=4.9, 2.0 Hz, 1H), 8.21 (dd,J=7.4, 2.0 Hz, 1H), 8.14 (dd, J=5.0, 1.9 Hz, 1H), 7.59 (dd, J=7.2, 1.8Hz, 1H), 7.05 (dd, J=7.4, 4.9 Hz, 1H), 6.97 (s, 1H), 6.90 (dd, J=7.2,5.0 Hz, 1H), 5.11 (t, J=5.8 Hz, 1H), 4.86 (hept, J=6.5 Hz, 1H), 4.48 (d,J=5.8 Hz, 2H), 4.39-4.34 (m, 1H), 4.04 (s, 3H), 2.63 (s, 3H), 1.63 (d,J=6.6 Hz, 6H), 0.79-0.76 (m, 2H), 0.63-0.60 (m, 2H). LC-MS (m/z) 445.5(MH⁺); t_(R)=0.6 minutes (Method D).

SUPPORTING EXAMPLE S1751-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from 5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-methoxypyridin-3-yl)methanamine and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ¹HNMR (Chloroform-d, 600 MHz) δ 8.15 (dd, J=5.1, 1.9 Hz, 1H), 7.60 (dd,J=7.2, 1.8 Hz, 1H), 7.48 (d, J=1.9 Hz, 1H), 6.91 (dd, J=7.2, 5.0 Hz,1H), 6.64 (s, 1H), 6.44 (d, J=2.0 Hz, 1H), 5.22 (t, J=5.9 Hz, 1H), 4.84(hept, J=6.6 Hz, 1H), 4.49 (d, J=5.8 Hz, 2H), 4.22 (s, 3H), 4.04 (s,3H), 2.60 (s, 3H), 1.63 (d, J=6.5 Hz, 6H). LC-MS (m/z) 392.5 (MH⁺);t_(R)=0.49 minutes (Method D).

SUPPORTING EXAMPLE S1765-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(5-methoxypyrimidin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from 5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(5-methoxypyrimidin-2-yl)methanamine and (2-ethoxy-3-pyridyl)boronicacid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.48 (s, 2H), 8.27 (d, J=7.6 Hz, 1H),8.20 (d, J=4.0 Hz, 1H), 7.16(s, 1H), 7.04 (dd, J=4.8, 6.8 Hz, 1H),5.15-5.08 (m, 1H), 4.68 (d, J=4.4 Hz, 2H), 4.50 (q, J=7.2 Hz, 2H), 3.98(s, 3H), 2.70 (s, 3H), 1.71 (d, J=6.4 Hz, 6H), 1.45 (t, J=6.8 Hz, 3H).LC-MS (m/z) 434.1 (MH⁺); t_(R)=2.15 minutes (Method C).

SUPPORTING EXAMPLE S1773-[1-isopropyl-3-methyl-7-[(1-methylpyrazol-4-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one

Prepared using the same procedure as described for supporting example 1from 5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(1-methyl-1H-pyrazol-4-yl)methanamine and(2-oxo-1,2-dihydropyridin-3-yl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.22 (d, J=6.8 Hz, 1H), 7.90-7.75 (m,1H), 7.59 (s, 1H), 7.57 (s, 1H), 7.26-7.20 (m, 1H), 6.65-6.63 (m, 1H),5.47 (brs, 1H), 4.96-4.90 (m, 1H), 4.52 (d, J=4.4 Hz, 2H), 3.92 (s, 3H),2.60 (s, 3H), 1.59 (d, J=6.4 Hz, 6H). LC-MS (m/z) 378 (MH⁺); t_(R)=1.71minutes (Method C).

SUPPORTING EXAMPLE S178N-[[2-(difluoromethyl)-3-pyridyl]methyl]-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from 5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-(difluoromethyl)pyridin-3-yl)methanamine and(2-ethoxy-3-pyridyl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.58 (d, J=4.4 Hz, 1H), 8.24 (dd,J=7.6, 2.0 Hz, 1H), 8.14 (dd, J=4.8, 2.0 Hz, 1H), 7.92 (d, J=7.6 Hz,1H), 7.42 (dd, J=8.0, 5.2 Hz, 1H), 7.13 (s, 1H), 7.00 (dd, J=7.2, 4.8Hz, 1H), 6.80 (t, J=54.8 Hz, 1H), 4.97-4.82 (m, 4H), 4.33 (q, J=6.8 Hz,2H), 2.66 (s, 3H), 1.64 (d, J=6.4 Hz, 6H), 1.21 (t, J=6.8 Hz, 3H) LC-MS(m/z) 453.1 (MH⁺); t_(R)=1.98 minutes (Method A).

SUPPORTING EXAMPLE S1795-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(6-methoxypyrimidin-4-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from 5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(6-methoxypyrimidin-4-yl)methanamine and (2-ethoxy-3-pyridyl)boronicacid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.82 (s, 1H), 8.25 (dd, J=5.2, 7.2 Hz,1H), 8.17 (dd, J=2.0, 5.2 Hz, 1H), 7.08 (s, 1H), 7.02 (dd, J=4.8, 7.2Hz, 1H), 6.78 (s, 1H), 6.01 (brs, 1H), 5.06-5.00 (m, 1H), 4.54 (d, J=4.4Hz, 2H), 4.43 (q, J=6.8 Hz, 2H), 4.01 (s, 3H), 2.66 (s, 3H), 1.69 (d,J=6.8 Hz, 6H), 1.36 (t, J=6.8 Hz, 3H) LC-MS (m/z) 434.1 (MH⁺); t_(R)=1.9minutes (Method A).

SUPPORTING EXAMPLE S1805-(2-(ethoxy-1,1-d₂)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from5-bromo-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand2-(ethoxy-1,1-d₂)-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2yl)pyridine.

¹H NMR (Chloroform-d, 600 MHz) δ 8.24 (dd, J=7.3, 2.0 Hz, 1H), 8.12-8.15(m, 2H), 7.59 (ddt, J=7.2, 1.8, 0.8 Hz, 1H), 7.14 (s, 1H), 6.99 (dd,J=7.4, 4.9 Hz, 1H), 6.89 (dd, J=7.2, 5.0 Hz, 1H), 5.10 (t, J=5.8 Hz,1H), 4.87 (hept, J=6.6 Hz, 1H), 4.50 (d, J=5.7 Hz, 2H), 4.03 (s, 3H),2.64 (s, 3H), 1.63 (d, J=6.5 Hz, 6H), 1.29 (s, 3H). LC-MS (m/z) 435.6(MH⁺); t_(R)=0.61 minutes (Method D).

SUPPORTING EXAMPLE S1815-(2-(ethoxy-ds)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from5-bromo-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 2-(ethoxy-d₅)-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2yl)pyridine.

¹H NMR (Chloroform-d, 600 MHz) δ 8.24 (ddd, J=7.4, 2.0, 0.7 Hz, 1H),8.12-8.15 (m, 2H), 7.61-7.56 (m, 1H), 7.14 (s, 1H), 7.02-6.96 (m, 1H),6.89 (dd, J=7.2, 5.0 Hz, 1H), 5.10 (t, J=5.8 Hz, 1H), 4.87 (hept, J=6.6Hz, 1H), 4.50 (d, J=5.7 Hz, 2H), 4.03 (s, 3H), 2.64 (s, 3H), 1.63 (d,J=6.5 Hz, 6H). LC-MS (m/z) 438.6 (MH⁺); t_(R)=0.6 minutes (Method D).

SUPPORTING EXAMPLE S1825-(2-(ethoxy-2,2,2-d3)pyridin-3-yl)-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from5-bromo-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand2-(ethoxy-2,2,2-d₃)-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaboran-2yl)pyridine.

¹H NMR (Chloroform-d, 600 MHz) δ 8.24 (dd, J=7.4, 2.0 Hz, 1H), 8.12-8.16(m, 2H), 7.59 (ddd, J=7.3, 1.9, 0.9 Hz, 1H), 7.14 (s, 1H), 6.99 (dd,J=7.4, 4.9 Hz, 1H), 6.89 (dd, J=7.2, 5.0 Hz, 1H), 5.10 (t, J=5.8 Hz,1H), 4.87 (hept, J=6.6 Hz, 1H), 4.50 (d, J=5.7 Hz, 2H), 4.38 (s, 2H),4.03 (s, 3H), 2.64 (s, 3H), 1.63 (d, J=6.5 Hz, 6H). LC-MS (m/z) 436.6(MH⁺); t_(R)=0.6 minutes (Method D).

SUPPORTING EXAMPLE S1831-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-5-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from5-bromo-1-isopropyl-N-((2-methoxypyridin-3-yl)methyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine and (2-(trifluoromethyl)pyridin-3-yl)boronic acid.

¹H NMR (Chloroform-d, 600 MHz) δ 8.73 (dd, J=4.7, 1.6 Hz, 1H), 8.13 (dd,J=5.1, 1.9 Hz, 1H), 7.94 (dd, J=7.9, 1.6 Hz, 1H), 7.57-7.52 (m, 2H),6.89 (dd, J=7.2, 5.1 Hz, 1H), 6.49 (s, 1H), 5.29 (t, J=5.8 Hz, 1H), 4.87(hept, J=6.6 Hz, 1H), 4.45 (d, J=5.8 Hz, 2H), 4.01 (s, 3H), 2.61 (s,3H), 1.66 (d, J=6.5 Hz, 6H). LC-MS (m/z) 457.5 (MH⁺); t_(R)=0.56 minutes(Method D).

SUPPORTING EXAMPLE S1843-(difluoromethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

A solution of7-chloro-3-(difluoromethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine(3.0 mg, 6.5 μmol), (1-methyl-1H-pyrazol-4-yl)methanamine (29.0 mg, 0.26mmol) in NMP (0.22 ml) in a sealed vial was inserted in an oil bath at155° C. and stirred for 16 hours The mixture was partitioned betweenethyl acetate (20 ml) and water (2×15 ml). The organic layer was washedwith brine (10 ml), dried (Na₂SO₄) and concentrated. Flashchromatography on silica gel (elution gradient from heptane to ethylacetate) delivered3-(difluoromethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d, 600 MHz) δ 8.33 (dd, J=7.4, 2.0 Hz, 1H), 8.18 (dd,J=4.9, 2.0 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 1H), 7.35 (s, 1H), 7.16 (t,J=54.1 Hz, 1H), 7.03 (dd, J=7.4, 4.9 Hz, 1H), 4.82 (hept, J=6.5 Hz, 1H),4.57 (t, J=5.0 Hz, 1H), 4.47 (q, J=7.0 Hz, 2H), 4.40 (d, J=4.8 Hz, 2H),3.93 (s, 3H), 1.64 (d, J=6.5 Hz, 6H), 1.39 (t, J=7.0 Hz, 3H). LC-MS(m/z) 442.6 (MH⁺); t_(R)=0.55 minutes (Method D).

SUPPORTING EXAMPLE S1851-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(1H-1,2,4-triazol-1-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

A mixture of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(50 mg, 0.14 mmol), 1H-1,2,4-triazole (19 mg, 0.28 mmol), Cs₂CO₃ (135mg, 0.41 mmol) Ni,N2-dimethylethane-1,2-diamine (2 mg, 0.028 mmol),iodocopper;tetrabutylammonium;diiodide (30 mg, 0.027 mmol) indimethylacetamide (2 mL) was stirred at 110° C. for 16 hours in a glovebox. After a filtration, the filtrate was concentrated and purified bypreparative HPLC to give1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(1H-1,2,4-triazol-1-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine.¹H NMR (Chloroform-d, 400 MHz):δ 9.24 (s, 1H), 8.08 (s, 1H), 7.58 (s,1H), 7.47 (s, 1H), 7.13 (s, 1H), 4.76-4.73 (m, 1H), 4.73-4.64 (m, 1H),4.45 (d, J=4.8 Hz, 2H), 3.95 (s, 3H), 2.59 (s, 3H), 1.59 (d, J=6.4 Hz,6H). LC-MS: t_(R)=1.88 min (Method B), m/z=352.1 [M+H]⁺.

SUPPORTING EXAMPLE S1863-[1-isopropyl-3-methyl-7-[(1-methyl-1,2,4-triazol-3-yl)methylamino]pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one

Prepared using the same procedure as described for supporting example 29from3-(7-amino-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2(1H)-oneand 1-methyl-1H-1,2,4-triazole-3-carbaldehyde.

¹H NMR (Chloroform-d, 400 MHz): δ 8.24-8.22 (m, 1H), 8.05 (s, 1H),8.02-7.98 (m, 1H), 7.21 (s, 1H), 6.79-6.74 (m, 1H), 6.00-5.94 (m, 1H),5.03-4.97 (m, 1H), 4.70 (d, J=4.4 Hz, 2H), 3.95 (s, 3H), 2.62 (s, 3H),1.65 (d, J=6.8 Hz, 6H). LC-MS (m/z) 379.1 (MH⁺); t_(R)=1.56 minutes(Method B).

SUPPORTING EXAMPLE S1873-[1-isopropyl-3-methyl-7-(1H-pyrazol-3-ylmethylamino)pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one

Prepared using the same procedure as described for supporting example 29from3-(7-amino-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-2(1H)-oneand 1H-pyrazole-3-carbaldehyde.

¹H NMR (DMSO-d₆, 400 MHz): δ 12.63 (brs, 1H), 11.73 (brs, 1H), 8.30-8.28(m, 1H), 7.82-7.47 (m, 3H), 6.62-6.51 (m, 1H), 6.32-6.21 (m, 2H),5.16-5.13 (m, 1H), 4.57-4.39 (m, 2H), 2.46 (s, 3H), 1.43 (d, J=6.4 Hz,6H). LC-MS (m/z) 364 (MH⁺); t_(R)=1.79 minutes (Method C).

SUPPORTING EXAMPLE S1885-[2-(difluoromethoxy)-3-pyridyl]-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from 5,7-dibromo-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-methoxypyridin-3-yl)methanamine and(2-(difluoromethoxy)pyridin-3-yl)boronic acid. ¹H NMR (Chloroform-d, 600MHz) δ 8.38 (dd, J=7.5, 2.0 Hz, 1H), 8.19 (dd, J=4.8, 2.0 Hz, 1H), 8.12(dd, J=5.1, 1.9 Hz, 1H), 7.64 (dd, J=7.2, 1.7 Hz, 1H), 7.60 (t, J=73.1Hz, 1H), 7.24 (dd, J=7.5, 4.8 Hz, 1H), 7.05 (s, 1H), 6.90 (dd, J=7.2,5.0 Hz, 1H), 5.27 (t, J=6.0 Hz, 1H), 4.87 (hept, J=6.5 Hz, 1H), 4.51 (d,J=5.9 Hz, 2H), 4.03 (s, 3H), 2.62 (s, 3H), 1.64 (d, J=6.6 Hz, 6H). LC-MS(m/z) 455.6 (MH⁺); t_(R)=0.57 minutes (Method D).

SUPPORTING EXAMPLE S1895-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxypyrimidin-2-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from 5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(4-methoxypyrimidin-2-yl)methanamine and (2-ethoxy-3-pyridyl)boronicacid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.47 (d, J=5.6 Hz, 1H), 8.26 (dd,J=2.0, 7.6 Hz, 1H), 8.19 (dd, J=2.0, 4.8 Hz, 1H), 7.17 (s, 1H), 7.03(dd, J=4.8, 7.2 Hz, 1H), 6.71 (d, J=6.0 Hz, 1H), 6.35 (brs, 1H),5.16-5.10 (m, 1H), 4.62 (d, J=4.4 Hz, 2H), 4.50 (q, J=6.8 Hz, 2H), 4.04(s, 3H), 2.67 (s, 3H), 1.69 (d, J=6.4 Hz, 6H), 1.46 (t, J=6.8 Hz, 3H)LC-MS (m/z) 434.2 (MH⁺); t_(R)=1.75 minutes (Method A).

SUPPORTING EXAMPLE S1905-(2-ethoxy-3-pyridyl)-1-isopropyl-N-[(4-methoxypyrimidin-5-yl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example165 from5-(2-ethoxypyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 5-(bromomethyl)-4-methoxypyrimidine.

¹H NMR (Chloroform-d, 400 MHz): δ 8.77 (s, 1H), 8.49 (s, 1H), 8.24 (dd,J=2.0, 7.2 Hz, 1H), 8.17 (dd, J=2.0, 4.8 Hz, 1H), 7.16 (s, 1H), 7.02(dd, J=4.8, 7.2 Hz, 1H), 4.97-4.94 (m, 1H), 4.88-4.84 (m, 1H), 4.52 (d,J=5.6 Hz, 2H), 4.44 (q, J=7.2 Hz, 2H), 4.09 (s, 3H), 2.65 (s, 3H), 1.64(d, J=6.8 Hz, 6H), 1.34 (t, J=6.8 Hz, 3H). LC-MS (m/z) 434.1 (MH⁺);t_(R)=1.57 minutes (Method A).

SUPPORTING EXAMPLE S1915-(2-ethoxy-3-pyridyl)-N-[(2-ethoxy-3-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from 5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-ethoxypyridin-3-yl)methanamine and (2-ethoxy-3-pyridyl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.26-8.24 (m, 1H), 8.17-8.16 (m, 1H),8.12-8.11 (m, 1H), 7.60-7.59 (m, 1H), 7.17 (s, 1H), 7.03-7.00 (m, 1H),6.88-6.87 (m, 1H), 5.08 (brs, 1H), 4.89-4.86 (m, 1H), 4.53-4.45 (m, 4H),4.41 (q, J=6.8 Hz, 2H), 2.65 (s, 3H), 1.64 (d, J=6.4 Hz, 6H), 1.43 (t,J=7.2 Hz, 3H), 1.32 (t, J=7.2 Hz, 3H). LC-MS (m/z) 447.2 (MH⁺);t_(R)=1.9 minutes (Method A).

SUPPORTING EXAMPLE S1925-[2-(dimethylamino)-3-pyridyl]-1-isopropyl-N-[(4-methoxyphenyl)methyl]-3-methyl-pyrazolo[4,3-b]pyridin-7-amine

To a solution of NaH (183 mg, 4.59 mmol, 60% w/w) in THF (4 mL) wasadded5-(2-fluoropyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine(310 mg, 0.77 mmol) at 0° C. Dimethylamine hydrochloride (156 mg, 1.91mmol) was added and the resulting mixture was stirred at 70° C. for 16hours. Water (3 mL) was added and the mixture was poured into asaturated, aqueous solution of NaHCO3. The mixture was extracted withethyl acetate (20 mL×3). The combined organic layers were washed withbrine (20 mL), dried over Na₂SO₄ and concentrated. The crude mixture waspurified by flash chromatography with heptane:ethyl acetate=1:0 to 0:1to give5-(2-(dimethylamino)pyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

¹H NMR (Chloroform-d, 600 MHz) δ 8.19 (dd, J=4.8, 1.9 Hz, 1H), 7.82 (dd,J=7.4, 1.9 Hz, 1H), 7.32 (d, J=8.6 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 6.82(dd, J=7.4, 4.8 Hz, 1H), 6.79 (s, 1H), 4.87-4.83 (m, 1H), 4.83-4.79 (m,1H), 4.42 (d, J=5.1 Hz, 2H), 3.83 (s, 3H), 2.64 (s, 3H), 2.61 (s, 6H),1.64 (d, J=6.6 Hz, 6H). LC-MS (m/z) 431.2 (MH⁺); t_(R)=0.42 minutes(Method D).

SUPPORTING EXAMPLE S1933-[1-isopropyl-3-methyl-7-[[2-(trifluoromethyl)-3-pyridyl]methylamino]pyrazolo[4,3-b]pyridin-5-yl]-1H-pyridin-2-one

Prepared using the same procedure as described for supporting example 1from 5,7-dichloro-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridine,(2-(trifluoromethyl)pyridin-3-yl)methanamine and(2-oxo-1,2-dihydropyridin-3-yl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.64 (d, J=4.4 Hz, 1H), 8.08 (d, J=8.0Hz, 2H), 7.69 (m,1H), 7.50-7.47 (m, 1H), 7.07 (m, 1H), 6.59-6.56 (m,1H), 6.06 (brs, 1H), 5.08 (m, 1H), 4.91 (s, 2H), 2.58 (s, 3H), 1.63 (d,J=6.4 Hz, 6H). LC-MS (m/z) 443 (MH⁺); t_(R)=1.87 minutes (Method C).

SUPPORTING EXAMPLE S1941-isopropyl-3-methyl-5-(3-methylisoxazol-4-yl)-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole.

¹H NMR (Chloroform-d, 400 MHz):δ=8.67 (s, 1H), 7.56 (s, 1H), 7.43 (s,1H), 6.54 (s, 1H), 4.79-4.66 (m, 1H), 4.60 (brs, 1H), 4.38 (d, J=4.8 Hz,2H), 3.94 (s, 3H), 2.61 (s, 6H), 1.59 (d, J=6.4 Hz, 6H). LC-MS (m/z)366.1 (MH⁺); t_(R)=1.61 minutes (Method C).

SUPPORTING EXAMPLE S1951-isopropyl-3-methyl-5-(1-methyl-1H-1,2,4-triazol-5-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

A mixture of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(0.15 g, 0.41 mmol), 1-methyl-1H-1,2,4-triazole (103 mg, 1.24 mmol),Pd(OAc)₂ (5 mg, 0.021 mmol), Ru-Phos(2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl) (19 mg, 0.041mmol), K₂CO₃ (171 mg, 1.24 mmol) and 2,2-dimethylpropanoic acid (21 mg,0.21 mmol) in xylene (15 mL) was stirred at 140° C. for 12 hours underN₂. The mixture was concentrated under vacuum. The residue was purifiedby preparative TLC (SiO₂, ethyl acetate/MeOH=10:1) and preparative HPLCto afford1-isopropyl-3-methyl-5-(1-methyl-1H-1,2,4-triazol-5-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d,; 400 MHz): δ 7.92 (s, 1H), 7.57 (s, 1H), 7.46 (s,1H), 7.42 (s, 1H), 4.76-4.70 (m, 1H), 4.59-4.56 (m, 1H), 4.47 (s, 3H),4.44 (d, J=4.4 Hz, 2H), 3.93 (s, 3H), 2.62 (s, 3H), 1.59 (d, J=6.4 Hz,6H). LC-MS (m/z) 366.1 (MH⁺); t_(R)=1.72 minutes (Method C).

SUPPORTING EXAMPLE S1961-isopropyl-3-methyl-5-(2-propoxy-3-pyridyl)-N-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 29from1-isopropyl-3-methyl-5-(2-propoxypyridin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-trityl-1H-pyrazole-4-carbaldehyde.

¹H NMR (DMSO-d₆, 400 MHz): δ 8.27 (dd, J=7.2, 2.0 Hz, 1H), 8.18 (dd,J=4.8, 2.0 Hz, 1H), 7.70 (s, 2H), 7.24 (s, 1H), 7.03 (dd, J=7.6, 5.2 Hz,1H), 4.82-4.72 (m, 1H), 4.52 (brs, 1H), 4.45 (d, J=4.8 Hz, 2H), 4.37 (t,J=6.4 Hz, 2H), 2.65 (s, 3H), 1.86-1.77 (m, 2H), 1.6 (d, J=6.4 Hz, 6H),1.04 (t, J=7.6 Hz, 3H). LC-MS (m/z) 406.1 (MH⁺); t_(R)=1.66 minutes(Method A).

SUPPORTING EXAMPLE S1975-(2-ethoxy-3-pyridyl)-N-[(2-methoxy-3-pyridyl)methyl]-3-methyl-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 1from 5,7-dibromo-3-methyl-1-(oxetan-3-yl)pyrazolo[4,3-b]pyridine,(2-methoxy-3-pyridyl)methanamine and (2-ethoxy-3-pyridyl)boronic acid.

¹H NMR (Chloroform-d, 400 MHz): δ 8.27 (dd, J=2.0, 7.6 Hz, 1H),8.19-8.16 (m, 1H), 8.15-8.12 (m, 1H), 7.59 (d, J=6.4 Hz 1H), 7.23 (s,1H), 7.04-7.01 (m, 1H), 6.91-6.88 (m, 1H), 6.15 (brs, 1H), 5.90-5.86 (m,1H), 5.26-5.22 (m, 2H), 5.18-5.15 (m, 2H), 4.53 (d, J=5.6 Hz, 2H), 4.42(q, J=6.8 Hz, 2H) 4.03 (s, 3H), 2.64 (s, 3H), 1.32 (t, J=6.8 Hz, 3H).LC-MS (m/z) 447 (MH⁺); t_(R)=1.89 minutes (Method C).

SUPPORTING EXAMPLE S1985-(2-(ethyl(methyl)amino)pyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example192 from5-(2-fluoropyridin-3-yl)-1-isopropyl-N-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand methylethanamine.

¹H NMR (Chloroform-d, 600 MHz) δ 8.20 (dd, J=4.8, 1.9 Hz, 1H), 7.80 (dd,J=7.4, 1.9 Hz, 1H), 7.32 (d, J=8.7 Hz, 2H), 6.93 (d, J=8.6 Hz, 2H),6.84-6.80 (m, 2H), 4.79 (hept, J=6.6 Hz, 1H), 4.72 (t, J=5.2 Hz, 1H),4.40 (d, J=5.1 Hz, 2H), 3.83 (s, 3H), 3.08 (q, J=7.0 Hz, 2H), 2.65 (s,3H), 2.64 (s, 3H), 1.62 (d, J=6.5 Hz, 6H), 0.93 (t, J=7.0 Hz, 3H). LC-MS(m/z) 445.6 (MH⁺); t_(R)=0.53 minutes (Method D).

SUPPORTING EXAMPLE S1995-(2-ethoxypyridin-3-yl)-3-(fluoromethyl)-1-isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine

A solution of7-chloro-5-(2-ethoxypyridin-3-yl)-3-(fluoromethyl)-1-isopropyl-1H-pyrazolo[4,3-b]pyridine(2.0 mg, 5.7 umol), (1-methyl-1H-pyrazol-4-yl)methanamine (30.0 mg, 0.27mmol) in NMP (0.2 ml) in a sealed vial was inserted in an oil bath at155° C. After 20 hours (1-methyl-1H-pyrazol-4-yl)methanamine (30.0 mg,0.27 mmol) was added and the solution was heated at 155° C. for 15hours. The mixture was partitioned between ethyl acetate (25 ml) andwater (3×20 ml). The organic layer was washed with brine (25 ml), dried(Na₂SO₄) and concentrated. The residue was purified by flashchromatography on silica gel (heptane/ethyl acetate) to give5-(2-ethoxypyridin-3-yl)-3-(fluoromethyl)-1-isopropyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (DMSO-d₆, 600 MHz) δ 8.21-8.15 (m, 2H), 7.61 (s, 1H), 7.42 (s,1H), 7.14 (s, 1H), 7.10 (dd, J=7.4, 4.9 Hz, 1H), 6.84 (t, J=5.6 Hz, 1H),5.67 (d, J=49.2 Hz, 2H), 5.28 (hept, J=6.4 Hz, 1H), 4.41-4.33 (m, 4H),3.77 (s, 3H), 1.51 (d, J=6.5 Hz, 6H), 1.24 (t, J=6.9 Hz, 3H). LC-MS(m/z) 424.6 (MH⁺); t_(R)=0.5 minutes (Method D).

SUPPORTING EXAMPLE S2001-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(4-methyloxazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

A mixture of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(0.15 g, 0.41 mmol), 4-methyloxazole (103 mg, 1.2 mmol), Pd(OAc)₂ (5 mg,0.021 mmol), Ru-Phos (19 mg, 0.041 mmol), K₂CO₃ (171 mg, 1.2 mmol) and2,2-dimethylpropanoic acid (17 mg, 0.17 mmol) in toluene (15 mL) wasstirred at 110° C. for 12 hours. The mixture was concentrated undervacuum. The residue was purified by preperative TLC (SiO₂, petroleumether/ethyl acetate=0:1) and preparative HPLC to afford1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(4-methyloxazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine.

¹H NMR (Chloroform-d,; 400 MHz): δ 7.85 (s, 1H), 7.58 (s, 1H), 7.45 (s,1H), 6.84 (s, 1H), 4.78-4.72 (m, 2H), 4.43 (d, J=4.4 Hz, 2H), 3.94 (s,3H), 2.68 (s, 3H), 2.62 (s, 3H), 1.58 (d, J=6.4 Hz, 6H). LC-MS (m/z) 366(MH⁺); t_(R)=1.6 minutes (Method C).

SUPPORTING EXAMPLE S2015-[2-(dimethylamino)-3-pyridyl]-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example 29from5-(2-(dimethylamino)pyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amineand 1-methyl-1H-pyrazole-4-carbaldehyde. ¹H NMR (Chloroform-d, 600 MHz)δ 8.22 (dd, J=4.8, 1.9 Hz, 1H), 7.83 (dd, J=7.3, 1.9 Hz, 1H), 7.54 (s,1H), 7.40 (s, 1H), 6.87-6.82 (m, 2H), 4.77 (hept, J=6.6 Hz, 1H), 4.58(t, J=4.7 Hz, 1H), 4.33 (d, J=5.0 Hz, 2H), 3.93 (s, 3H), 2.73 (s, 6H),2.64 (s, 3H), 1.61 (d, J=6.6 Hz, 6H). LC-MS (m/z) 405.6 (MH⁺);t_(R)=0.34 minutes (Method D).

SUPPORTING EXAMPLE S2021-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(4-methyloxazol-2-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine

A mixture of5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amine(100 mg, 0.28 mmol), 4-methyloxazole (46 mg, 0.55 mmol), XPHOS-Pd-G3((2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(11)methanesulfonate) (12 mg, 0.014 mmol), t-BuOK (93 mg, 0.83 mmol) indimethylacetamide (5 mL) was stirred at 100° C. for 12 hours under N₂.The mixture was concentrated under vacuum. The residue was purified bypreparative TLC (SiO₂, Petroleum ether/ethyl acetate=0:1) andpreparative HPLC to afford1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(4-methyloxazol-2-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine.¹H NMR (Chloroform-d,; 400 MHz): (5 7.58 (s, 1H), 7.53 (s, 1H), 7.45 (s,1H), 7.34 (s, 1H), 4.77-4.67 (m, 1H), 4.58 (brs, 1H), 4.44 (d, J=4.8 Hz,2H), 3.94 (s, 3H), 2.68 (s, 3H), 2.29 (s, 3H), 1.58 (d, J=6.8 Hz, 6H).LC-MS (m/z) 366.1 (MH⁺); t_(R)=1.74 minutes (Method C).

SUPPORTING EXAMPLE S2031-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(4-methyl-1,2,4-triazol-3-yl)pyrazolo[4,3-b]pyridin-7-amine

Prepared using the same procedure as described for supporting example195 from5-bromo-1-isopropyl-3-methyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-7-amineand 4-methyl-4H-1,2,4-triazole.

¹H NMR (CDCl₃ 400 MHz): δ 8.18 (s, 1H), 7.56 (s, 1H), 7.55 (s, 1H), 7.48(s, 1H), 4.78-4.71 (m, 1H), 4.60 (brs, 1H), 4.44 (d, J=4.4 Hz, 2H), 4.23(s, 3H), 3.93 (s, 3H), 2.60 (s, 3H), 1.59 (d, J=6.4 Hz, 6H). LC-MS (m/z)366.1 (MH⁺); t_(R)=1.65 minutes (Method B).

In Vitro Testing PDE1 Inhibition Assay

PDE1A, PDE1B and PDE1C assays were performed as follows: the assays wereperformed in 60 μL samples containing a fixed amount of the PDE1 enzyme(sufficient to convert 20-25% of the cyclic nucleotide substrate), abuffer (50 mM HEPES pH 7.6; 10 mM MgCl₂; 0.02% Tween20), 0.1 mg/ml BSA,15 nM tritium labelled cAMP and varying amounts of inhibitors. Reactionswere initiated by addition of the cyclic nucleotide substrate, andreactions were allowed to proceed for 1 hr at room temperature beforebeing terminated through mixing with 20 μL (0.2 mg) yttrium silicate SPAbeads (PerkinElmer). The beads were allowed to settle for 1 hr in thedark before the plates were counted in a Wallac 1450 Microbeta counter.The measured signals were converted to activity relative to anuninhibited control (100%) and ICso values were calculated using XIFit(model 205, IDBS).

1. A compound according to formula (I)

wherein L is selected from the group consisting of NH, CH₂, S and O; R1is selected from the group consisting of hydrogen, linear or branchedC₁₋₅ alkyl, C₁₋₅ fluoroalkyl and saturated monocyclic C₃₋₅ cycloalkyl;R2 is selected from the group consisting of linear or branched C₁₋₈alkyl, saturated monocyclic C₃₋₈ cycloalkyl, oxetanyl,tetrahydrofuranyl, and tetrahydropyranyl; all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of methyl, fluorine, hydroxy, cyano andmethoxy; the combination of R3 and R4 are selected from a) and b): a) R3is methyl substituted with a 9-membered bicyclic heteroaryl which isoptionally substituted with one or more substituents selected fromhalogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃alkoxy; or R3 is ethyl substituted with a 9-membered bicyclic heteroarylwhich is optionally substituted with one or more substituents selectedfrom halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy andC₁₋₃ alkoxy; or L is CH₂ and R3 is NH which is substituted with a9-membered bicyclic heteroaryl which is optionally substituted with oneor more substituents selected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; R4 is phenyl, pyridinyl,pyridazinyl or pyridonyl all of which can be optionally substituted oneor more times with one or more substituents selected from the groupconsisting of halogen, cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃deuterioalkoxy and —N—R5R6 wherein R5 and R6 are each independentlyselected from H, C₁₋₃ alkyl and C₁₋₃ deuterioalkyl; or R4 is a5-membered heteroaryl which is optionally substituted with one or moresubstituents selected from halogen, cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl,C₁₋₄ deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃deuterioalkoxy and —N—R5R6 wherein R5 and R6 are each independentlyselected from H, C₁₋₃ alkyl and C₁₋₃ deuterioalkyl; or R4 is a 4, 5 or 6membered saturated heterocycle all of which can be optionallysubstituted with one or more substituents selected from oxo, C₁₋₄ alkyland C₁₋₄ fluoroalkyl; b) R3 is methyl substituted with phenyl,pyridonyl, pyridinyl, pyrimidinyl or pyrazinyl all of which can beoptionally substituted one or more times with one or more substituentsselected from the group consisting of halogen, cyano, C1-3 alkyl, C1-3fluoroalkyl, C1-3 fluoroalkoxy and C1-3 alkoxy; or R3 is methylsubstituted with a 5-membered heteroaryl which is optionally substitutedwith one or more substituents selected from halogen, cyano, C₁₋₃ alkyl,C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or R3 is ethylsubstituted with phenyl, pyridonyl, pyridinyl, pyrimidinyl or pyrazinylall of which can be optionally substituted one or more times with one ormore substituents selected from the group consisting of halogen, cyano,C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or R3is ethyl substituted with a 5-membered heteroaryl which is optionallysubstituted with one or more substituents selected from halogen, cyano,C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or L isCH₂ and R3 is NH which is substituted with phenyl, pyridonyl, pyridinyl,pyrimidinyl or pyrazinyl all of which can be optionally substituted oneor more times with one or more substituents selected from the groupconsisting of halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃fluoroalkoxy and C₁₋₃ alkoxy; or L is CH₂ and R3 is NH which issubstituted with a 5-membered heteroaryl which is optionally substitutedwith one or more substituents selected from halogen, cyano, C₁₋₃ alkyl,C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; R4 is pyridazinylwhich can be optionally substituted one or more times with one or moresubstituents selected from the group consisting of halogen, cyano, C₁₋₄alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ deuterioalkyl, C₁₋₃ fluoroalkoxy,cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6 wherein R5and R6 are each independently selected from H, C₁₋₃ alkyl and C₁₋₃deuterioalkyl; or R4 is 4-pyridinyl which can be optionally substitutedone or more times with one or more substituents selected from the groupconsisting of halogen, cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃deuterioalkoxy and —N—R5R6 wherein R5 and R6 are each independentlyselected from H, C₁₋₃ alkyl and C₁₋₃ deuterioalkyl; or R4 is a9-membered bicyclic heteroaryl which can be optionally substituted oneor more times with one or more substituents selected from the groupconsisting of halogen, cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃deuterioalkoxy and —N—R5R6 wherein R5 and R6 are each independentlyselected from H, C₁₋₃ alkyl and C₁₋₃ deuterioalkyl; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 of formula (Ia)

wherein L is selected from the group consisting of NH, CH₂, S and O; R1is selected from the group consisting of hydrogen, linear or branchedC₁₋₅ alkyl, C₁₋₅ fluoroalkyl and saturated monocyclic C₃₋₅ cycloalkyl;R2 is selected from the group consisting of linear or branched C₁₋₈alkyl, saturated monocyclic C₃₋₈ cycloalkyl, oxetanyl,tetrahydrofuranyl, and tetrahydropyranyl; all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of methyl, fluorine, hydroxy, cyano andmethoxy; R3 is methyl substituted with a 9-membered bicyclic heteroarylwhich is optionally substituted with one or more substituents selectedfrom halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy andC₁₋₃ alkoxy; or R3 is ethyl substituted with a 9-membered bicyclicheteroaryl which is optionally substituted with one or more substituentsselected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃fluoroalkoxy and C₁₋₃ alkoxy; or L is CH₂ and R3 is NH which issubstituted with a 9-membered bicyclic heteroaryl which is optionallysubstituted with one or more substituents selected from halogen, cyano,C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; R4 isphenyl, pyridinyl, pyridazinyl or pyridonyl all of which can beoptionally substituted one or more times with one or more substituentsselected from the group consisting of halogen, cyano, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, C₁₋₄ deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6 wherein R5 and R6 are eachindependently selected from H, C₁₋₃ alkyl and C₁₋₃ deuterioalkyl; or R4is a 5-membered heteroaryl which is optionally substituted with one ormore substituents selected from halogen, cyano, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, C₁₋₄ deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6 wherein R5 and R6 are eachindependently selected from H, C₁₋₃ alkyl and C₁₋₃ deuterioalkyl; or R4is a 4, 5 or 6 membered saturated heterocycle all of which can beoptionally substituted with one or more substituents selected from oxo,C₁₋₄ alkyl and C₁₋₄ fluoroalkyl; or a pharmaceutically acceptable saltthereof.
 3. A compound according to claim 1 of formula (Ib)

wherein L is selected from the group consisting of NH, CH₂, S and O; R1is selected from the group consisting of hydrogen, linear or branchedC₁₋₅ alkyl, C₁₋₅ fluoroalkyl and saturated monocyclic C₃₋₅ cycloalkyl;R2 is selected from the group consisting of linear or branched C₁₋₈alkyl, saturated monocyclic C₃₋₈ cycloalkyl, oxetanyl,tetrahydrofuranyl, and tetrahydropyranyl; all of which can be optionallysubstituted one or more times with one or more substituents selectedfrom the group consisting of methyl, fluorine, hydroxy, cyano andmethoxy; R3 is methyl substituted with phenyl, pyridonyl, pyridinyl,pyrimidinyl or pyrazinyl all of which can be optionally substituted oneor more times with one or more substituents selected from the groupconsisting of halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃fluoroalkoxy and C₁₋₃ alkoxy; or R3 is methyl substituted with a5-membered heteroaryl which is optionally substituted with one or moresubstituents selected from halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl,C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or R3 is ethyl substituted withphenyl, pyridonyl, pyridinyl, pyrimidinyl or pyrazinyl all of which canbe optionally substituted one or more times with one or moresubstituents selected from the group consisting of halogen, cyano, C₁₋₃alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or R3 isethyl substituted with a 5-membered heteroaryl which is optionallysubstituted with one or more substituents selected from halogen, cyano,C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; or L isCH₂ and R3 is NH which is substituted with phenyl, pyridonyl, pyridinyl,pyrimidinyl or pyrazinyl all of which can be optionally substituted oneor more times with one or more substituents selected from the groupconsisting of halogen, cyano, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, C₁₋₃fluoroalkoxy and C₁₋₃ alkoxy; or L is CH₂ and R3 is NH which issubstituted with a 5-membered heteroaryl which is optionally substitutedwith one or more substituents selected from halogen, cyano, C₁₋₃ alkyl,C₁₋₃ fluoroalkyl, C₁₋₃ fluoroalkoxy and C₁₋₃ alkoxy; R4 is pyridazinylwhich can be optionally substituted one or more times with one or moresubstituents selected from the group consisting of halogen, cyano, C₁₋₄alkyl, C₁₋₄ fluoroalkyl, C₁₋₄ deuterioalkyl, C₁₋₃ fluoroalkoxy,cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃ deuterioalkoxy and —N—R5R6 wherein R5and R6 are each independently selected from H, C₁₋₃ alkyl and C₁₋₃deuterioalkyl; or R4 is 4-pyridinyl which can be optionally substitutedone or more times with one or more substituents selected from the groupconsisting of halogen, cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃deuterioalkoxy and —N—R5R6 wherein R5 and R6 are each independentlyselected from H, C₁₋₃ alkyl and C₁₋₃ deuterioalkyl; or R4 is a9-membered bicyclic heteroaryl which can be optionally substituted oneor more times with one or more substituents selected from the groupconsisting of halogen, cyano, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₁₋₄deuterioalkyl, C₁₋₃ fluoroalkoxy, cyclopropyloxy, C₁₋₃ alkoxy, C₁₋₃deuterioalkoxy and —N—R5R6 wherein R5 and R6 are each independentlyselected from H, C₁₋₃ alkyl and C₁₋₃ deuterioalkyl; or apharmaceutically acceptable salt thereof.
 4. The compound according toclaim 1 wherein L is NH, or a pharmaceutically acceptable salt thereof.5. The compound according to claim 1 wherein R1 is methyl, or apharmaceutically acceptable salt thereof.
 6. The compound according toclaim 1 wherein R2 is a linear or branched C₁₋₈ alkyl, or apharmaceutically acceptable salt thereof.
 7. The compound according toclaim 1 of formula (Iaa)

wherein R1 is methyl; R2 is isopropyl; R3 is methyl substituted with a9-membered bicyclic heteroaryl which is optionally substituted withmethyl; R4 is pyridinyl which is optionally substituted with ethoxy or apharmaceutically acceptable salt thereof.
 8. The compound according toclaim 1 of formula(Ibb)

wherein R1 is methyl; R2 is linear or branched C₁₋₈ alkyl; R3 is methylsubstituted with phenyl, pyridonyl, pyridinyl, pyrimidinyl or pyrazinylall of which can be optionally substituted one or more times with one ormore substituents selected from the group consisting of fluorine, C₁₋₃alkyl and C₁₋₃ alkoxy; or R3 is methyl substituted with a 5-memberedheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of fluorine, C₁₋₃ alkyl and C₁₋₃alkoxy; R4 is pyridazinyl which can be optionally substituted once witha C₁₋₃ alkoxy; or R4 is 4-pyridinyl which can be optionally substitutedonce with a C₁₋₃ alkoxy; or R4 is a 9-membered bicyclic heteroaryl whichcan be optionally substituted once with a methyl; or a pharmaceuticallyacceptable salt thereof.
 9. The compound according to claim 1, whereinthe compound is selected from the group consisting of: 1a.5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;2a.N-(2,1,3-benzothiadiazol-4-ylmethyl)-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;3a.5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-([1,2,4]triazolo[4,3-a]pyridin-8-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;4a.5-(2-ethoxy-3-pyridyl)-N-(imidazo[1,2-a]pyridin-8-ylmethyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;5a.5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-(pyrazolo[1,5-a]pyridin-4-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;6a.5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-([1,2,4]triazolo[1,5-a]pyridin-5-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;7a.5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;8a.5-(2-ethoxy-3-pyridyl)-N-(imidazo[1,5-a]pyridin-8-ylmethyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;9a.N-(1,3-benzoxazol-7-ylmethyl)-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;10a.N-(1,3-benzoxazol-4-ylmethyl)-5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;11a.5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-1,3-benzoxazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;12a.5-(2-ethoxy-3-pyridyl)-1-isopropyl-3-methyl-N-[(2-methyl-1,3-benzoxazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;13a.N-(1,3-benzoxazol-4-ylmethyl)-5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;14a.5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(2-methyl-1,3-benzoxazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;15a.N-([1,2,4]triazolo[4,3-c]pyrimidin-5-ylmethyl)-5-(2-ethoxypyridin-3-yl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;16a.5-(2-ethoxypyridin-3-yl)-N-(imidazo[1,2-c]pyrimidin-5-ylmethyl)-1-isopropyl-3-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine;and pharmaceutically acceptable salts of any of these compounds.
 10. Thecompound according to claim 1, wherein the compound is selected from thegroup consisting of: 1b.5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-(pyrimidin-2-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;2b.1-isopropyl-5-(3-methoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;3b.5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;4b.1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(3-propoxypyridazin-4-yl)pyrazolo[4,3-b]pyridin-7-amine;5b.(R)-5-(3-ethoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yhmethyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amineor(S)-5-(3-ethoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;6b.(R)-5-(3-ethoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yhmethyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amineor(S)-5-(3-ethoxypyridazin-4-yl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;7b.5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methylpyrazolo[4,3-b]pyridin-7-amine;8b.5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;9b.5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;10b.5-(3-ethoxypyridazin-4-yl)-N-[(5-fluoropyrimidin-2-yl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;11b.5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(4-methylpyrimidin-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;12b.5-(3-ethoxy-4-pyridyl)-N-[(6-fluoro-2-pyridyl)methyl]-1-isopropyl-3-methyl-pyrazolo[4,3-b]pyridin-7-amine;13b.5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-(1H-pyrazol-3-ylmethyl)pyrazolo[4,3-b]pyridin-7-amine;14b.5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine;15b.5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-(2-pyridylmethyl)pyrazolo[4,3-b]pyridin-7-amine;16b.5-(3-ethoxypyridazin-4-yl)-N-[(2-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methylpyrazolo[4,3-b]pyridin-7-amine;17b.5-(3-ethoxy-4-pyridyl)-N-[(2-fluoro-3-pyridyl)methyl]-1-isopropyl-3-methylpyrazolo[4,3-b]pyridin-7-amine;18b.5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;19b.5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;20b.5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;21b.5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(2-methylthiazol-5-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;22b.5-(3-ethoxypyridazin-4-yl)-1-isopropyl-3-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;23b.5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;24b.5-(3-ethoxypyridazin-4-yl)-1-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-3-methylpyrazolo[4,3-b]pyridin-7-amine;25b.5-(3-ethoxy-4-pyridyl)-1-isopropyl-N-[(6-methoxy-2-pyridyl)methyl]-3-methylpyrazolo[4,3-b]pyridin-7-amine;26b.5-(3-ethoxypyridazin-4-yl)-N-[(6-fluoro-2-pyridyl)methyl]-1-isopropyl-3-methylpyrazolo[4,3-b]pyridin-7-amine;27b.5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;28b.5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;29b.1-isopropyl-5-(3-methoxy-4-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;30b.5-(3-ethoxy-4-pyridyl)-1-isopropyl-N-[(2-methoxy-3-pyridyl)methyl]-3-methylpyrazolo[4,3-b]pyridin-7-amine;31b.1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-5-(3-propoxy-4-pyridyl)pyrazolo[4,3-b]pyridin-7-amine;32b.(R)-5-(3-ethoxy-4-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amineor(S)-5-(3-ethoxy-4-pyridyl)-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-1-[1-methylpropyl]pyrazolo[4,3-b]pyridin-7-amine;34b.5-(3-ethoxy-4-pyridyl)-1-isopropyl-3-methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;35b.1-isopropyl-3-methyl-5-(2-methyl-1,3-benzoxazol-4-yl)-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;36b.1-isopropyl-3-methyl-5-(2-methyl-1,3-benzoxazol-7-yl)-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;37b.5-(1,3-benzoxazol-7-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;38b.5-(1H-indo1-7-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;39b.5-(1H-indazol-7-yl)-1-isopropyl-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]pyrazolo[4,3-b]pyridin-7-amine;and pharmaceutically acceptable salts of any of these compounds. 11.(canceled)
 12. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptablecarriers, diluents and/or excipients.
 13. (canceled)
 14. A method forthe treatment of a neurodegenerative disorder, selected from the groupconsisting of Alzheimer's Disease, Parkinson's Disease and Huntington'sDisease or for the treatment of a psychiatric disorder such as AttentionDeficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,cognitive impairment and cognitive impairment associated withschizophrenia (CIAS), or another brain disease like restless legsyndrome, which method comprises the administration of a therapeuticallyeffective amount of a compound according to claim 1, or apharmaceutically acceptable salt thereof, to a patient in need thereof.15. The compound according to claim 2 wherein L is NH, or apharmaceutically acceptable salt thereof.
 16. The compound according toclaim 3 wherein L is NH, or a pharmaceutically acceptable salt thereof.17. The compound according to claim 2, wherein R1 is methyl, or apharmaceutically acceptable salt thereof.
 18. The compound according toclaim 3, wherein R1 is methyl, or a pharmaceutically acceptable saltthereof.
 19. The compound according to claim 4, wherein R1 is methyl, ora pharmaceutically acceptable salt thereof.
 20. The compound accordingto claim 2 wherein R2 is a linear or branched C₁₋₈ alkyl, or apharmaceutically acceptable salt thereof.
 21. The compound according toclaim 3 wherein R2 is a linear or branched C₁₋₈ alkyl, or apharmaceutically acceptable salt thereof.
 22. The compound according toclaim 4 wherein R2 is a linear or branched C₁₋₈ alkyl, or apharmaceutically acceptable salt thereof.